A Quick Look at Biochemistry Lipid Metabolism 2155 6156.1000324 PDF

Dashty, J Diabetes Metab 2014, 5:1
http://dx.doi.org/10.4172/2155-6156.1000324
Diabetes & Metabolism
Open Access
Review Article
A Quick Look at Biochemistry: Lipid Metabolism

Monireh Dashty
Department of Cell Biology, University Medical Center Groningen, University of Groningen, The Netherlands
Abstract
Lipids and carbohydrates are the energetic molecules and one of the main components of the metabolic system.
These molecules circulate in the blood stream and between the metabolic tissues and transfer energy throughout
the body. They are degraded and release their energy in the form of Adenosine Triphosphate (ATP) to be used in
anabolic reactions. Anabolic reactions are the energy consumer reactions for synthesis of molecules or energy
storage. These include glycogenolysis, glycolysis, Tricarboxylic Acid (TCA, citric acid or the Krebs) cycle, electron
transfer chain, and fatty acid beta oxidation and protein breakdown. Carbohydrates are the main energetic molecules
that are consumed by active tissues like muscles. In excess consumption of carbohydrates, they are converted to
lipid molecules to be stored in the adipose tissue for the time of starvation. This matter is one of the most important
functions of the body in energy homeostasis. In this review, the main lipid groups are introduced and fat biochemical
pathways are highlighted and illustrated in a way to facilitate follow up of the lipid biochemical pathways and to give
the reader a better understanding of the pathogenesis of metabolic system disorders.
Keywords: Lipid; Carbohydrate; Lipoprotein; Atherosclerosis

Introduction
Lipids are a group of naturally occurring compounds and
hydrophobic or amphiphilic molecules that form structures such as
vesicles, liposomes or membranes in an aqueous environment. They
are a large and diverse group of organic macromolecules; hence, it is
always difficult for scientists to provide a specific definition for the word
lipid. Therefore, due to the absence of a widely-accepted definition
in this regard, lipids are categorized based on their different chemical
properties including their ability for saponification, their chemical
compositions and their building blocks. Saponification is the ability
of lipids to be hydrolyzed by basic solutions into compounds such as
glycerol and fatty acids (FAs). Based on their chemical composition,
lipids are classified into simple and complex lipids. Simple lipids contain
one or two different types of compounds. However, complex lipids
frequently consist of three or more chemical identities (e.g., glycerol,
FAs, and sugar) and they are usually amphipathic. Based on their
building-blocks, lipids are categorized into two ketoacyl and isoprene
groups. In this categorization, lipids are divided into eight categories
in which FAs, glycerolipids, glycerophospholipids, sphingolipids,
saccharolipids, and polyketides are derived from ketoacyl subunits and
sterol lipids and prenol lipids derived from isoprene subunits. Regardless
of all diversities in lipid classification, overlapping between different
classifications still exist. This section simply introduces definitions of
each category that is described in general books [1]. Nomenclatures,
abbreviations and formulas are explained in the text and figures 1 and 2.
Lipid Categorization and their Definitions

Lipids, fats and oils
Fats consist of a wide group of compounds with the same chemical
structure that are derivatives of FAs and glycerol bounded together
via ester bonds. For instance, triglycerides are triesters of glycerol
with three FAs. The properties of fats depend on their structure and
particularly on the composition of their FAs. Long chain FAs (LCFAs)
yield more energy per molecule during degradation and have a higher
melting point compared to short chain FAs. Therefore, fats may be
either solid or liquid at room temperature. Oils are referred to fats
that are liquid at normal room temperature, while fats are usually
solid at normal room temperature. Lipids is used to refer to both
J Diabetes Metab
ISSN: 2155-6156 JDM, an open access journal
Figure 1: Formulas.
*Corresponding author: Monireh Dashty, Department of Cell Biology, University

Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1,
9713 AV, Groningen, The Netherlands, Tel: +31 (0) 50 3632536; Fax: +31 (0) 50
3632522; E-mail: M.Dashti.Rahmatabadi@med.umcg.nl
Received November 26, 2013; Accepted January 02, 2014; Published January
07, 2014
Citation: Dashty M (2014) A Quick Look at Biochemistry: Lipid Metabolism. J
Diabetes Metab 2: 324. doi:10.4172/2155-6156.1000324
Copyright: 2014 Dashty M. This is an open-access article distributed under the
terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited.
Volume 5 Issue 1 1000324
Citation: Dashty M (2014) A Quick Look at Biochemistry: Lipid Metabolism. J Diabetes Metab 2: 324. doi:10.4172/2155-6156.1000324
Page 2 of 17
Chemically, FAs are categorized into saturated and unsaturated
forms. In saturated FAs (CnH(2n+1)COOH), their carbon chain is
saturated with hydrogen during hydrogenation process. Unsaturated
FAs (CnH(2n-1)COOH) contain double bonds within their carbon
chain. Monounsaturated FAs (MUFAs) have only one double bond
and polyunsaturated FAs (PUFAs or polyenoic fatty acids) contain
two or more double bonds. Unsaturated fats can be further divided
into Cis or Trans geometric isomers, which significantly affect the
molecules configuration, structure and function of cell membranes.
Most naturally occurring FAs are of the Cis configuration, while Trans
configuration significantly increases the risk of coronary heart disease.
Saturated and unsaturated forms differ in their energy content and
melting point. Energy that is yielded during metabolism of unsaturated
fats is less than that of saturated fats with the same number of carbon
atoms. Moreover, saturated fats are typically solid at room temperature,
while highly unsaturated fats are oily.
Acylglycerols (AGs)
Acylglycerols (glycerolipids, glycerides or neutral fats) are glycerol
esters of FAs. Esterification of one, two or three FAs with glycerol yield
monoacylglycerol (MAG), diacylglycerol (DAG) or triacylglycerol
(TAG). TAGs function as energy store in the adipose tissues that are
hydrolyzed to release glycerol and FAs for consumption of their energy
in the shortage of energy. The other molecules in this category are
glucosylglycerol (such as digalactosyldiacylglycerol and seminolipid),
which are molecules composed of sugar residues and glycerol.
Figure 2: Abbreviations.
liquid and solid fats that are not soluble in water. Oil is also used for
any substance that does not mix with water and has a greasy feel, for
instance petroleum, heating oil, and essential oil, regardless of its
chemical structure.
Fats are an important part of the diet and are broken down by
lipases and serve both structural and metabolic functions. They play
a vital role in energy storage in the body, health of skin and hair [2],
promoting cell function and protecting body organs against shock and
maintaining body temperature. They are sources of essential FAs and
are required for the function of fat-soluble vitamins (A, D, E and K). The
new fat tissues also function to dilute unsafe levels of substances in the
bloodstream by storing them in their adipocytes. This helps to protect
vital organs until the substances can be metabolized and/or removed
from the body. It is also a useful buffer towards a host of diseases [3].
Fatty acids
FAs (CH3(CH2)nCOOH) are amphipathic hydrocarbon chain
molecules synthesized using acetyl-CoA and malonyl-CoA. They are
terminated with a polar, hydrophilic carboxylic acid end and a nonpolar, hydrophobic end that is insoluble in water. They usually have an
even number of carbon atoms. FAs are used in other complex lipids
and may be attached to functional groups containing oxygen, nitrogen,
halogens and sulfur. Biologically important FAs are eicosanoids,
docosahexaenoic acid, fatty esters and fatty amides. Eicosanoids
include prostaglandins, leukotrienes, thromboxanes, which are
derived primarily from arachidonic acid and eicosapentaenoic acid.
Fatty esters include wax esters, FA thioester coenzyme A derivatives,
FA thioester ACP derivatives and FA carnitine. Fatty amides include
N-acylethanolamines, such as cannabinoid neurotransmitter
anandamide.
J Diabetes Metab
Waxes
Waxes are saponificable, very hydrophobic compounds that
are biosynthesized by many plants and animals. They are formed by
esterification of long chain FAs (alkyl groups) with hydroxyl group of
long chain fatty alcohols or lipid alcohols such as sterols, aminoalcohols,
hydroxycarotenoids or terpenols. They are organic compounds that are
plastic near ambient temperatures. Above 45C, they melt to produce
a low viscosity liquid. Natural waxes are a mixture of waxes and other
substances such as hydrocarbons, fatty alcohols, fatty aldehydes, FAs,
terpenes, etc, that form a protective coating in plants and animals
against desiccation and parasites. Synthetic waxes are long-chain
hydrocarbons lacking functional groups.
Phospholipids
Phospholipids are complex lipid molecules in which phosphate
group attaches to one alcohol that may be linked to fatty chains.
Phospholipids are the major structural constituents of all biological
membranes because they tend to form lipid bilayers corresponding to
their ionic head and hydrophobic tails. They also may be involved in
signal transduction. Phospholipids are classified into two main groups:
glycerophospholipids and sphingosyl phosphatides.
Glycerophospholipids are amphipathic molecules that are formed
by esterification of an alcohol to the phosphate of phosphatidic
acid (1,2 diacylglycerol 3-phosphate). They are found in the neural
tissue and lipid bilayer of cell and function in metabolism and cell
signaling. They are subdivided into phosphatidylcholine (PC or
lecithin), phosphatidylethanolamine (PE), phosphatidylserine (PS),
phosphatidylinositols (PI), phosphatidylglycerol (PG) and cardiolipin
or diphosphatidylglycerol (DPG). Plasmalogens are a group of
phospholipids in whose structure one fatty aldehyde is substituted by
the FA. Therefore, they are phosphatidyl molecules that are linked to
ethanolamine, choline, serine or inositol. Glycerophospholipids can be
hydrolyzed by phospholipases or by alkaline solutions.
Page 3 of 17
Sphingosyl phosphatides are lipids containing (sphingo)ceramides
linked by their hydroxyl group to a phosphate group, itself esterified to
a polar head group such as choline (in sphingomyelins), ethanolamine
and glycerol or to a glycoside moiety (in glycolipids)
Sphingolipids
Sphingolipids comprise a complex range of lipids in which FAs are
linked via amide bonds to a long-chain base or sphingoid. A sphingoid
base backbone is synthesized from serine and a long-chain fatty
acyl-CoA (palmitoyl-CoA). The major sphingoid base of mammals
is commonly referred to as sphingosine. Some sphingoid base
derivatives are ceramides, sphingomyelin (a phosphosphingolipids)
and glycosphingolipids. Ceramide is a product that is yielded by amidelinkage of FA to the sphingosine molecule. Combination of ceramide
with one molecule of phosphocholine produces sphingomyelin
(or ceramide phosphocholine). Glycosphingolipids are molecules
composed of one or more sugar residues linked to the sphingoid base
via a glycosidic bond. Examples of glycosphingolipids are cerebrosides,
globosides and gangliosides. Cerebrosides are made by glycosidic
linkage of the hydroxyl group of ceramide with one hexose molecule
(glucose or galactose). In globosides one hexose molecule is substituted
with dimmers. The molecular structures of gangliosides are similar to
cerebrosides. It has at least three sugars, one of which must be sialic acid.
Sphingolipids protect the cell surface against harmful environmental
factors. Certain complex glycosphingolipids are involved in cell
recognition and signaling. Ceramide and sphingosine-1-phosphate are
important mediators in the signaling cascades involved in apoptosis,
proliferation, stress responses, necrosis, inflammation, autophagy,
senescence, and differentiation. In experimental animals, feeding
sphingolipids inhibits colon carcinogenesis, reduces LDL cholesterol
and elevates HDL cholesterol.
developmental signaling as secondary messengers. The most important

sterols are cholesterol, which is an important component of membrane
lipids, along with the glycerophospholipids and sphingomyelins. Other
examples of sterols are bile acids and their conjugates, which in mammals
are oxidized derivatives of cholesterol and are synthesized in the liver.
Secosteroids, comprising different forms of vitamin D, are characterized
by cleavage of the B ring of the core structure. Steroids are important
components of cell membranes, hormones and vitamin D precursors.
Prenol lipids
Prenol lipids are compounds that are synthesized from the fivecarbon-unit precursor isopentenyl di (or pyro) phosphate (IPP)
and dimethylallyl diphosphate that are produced mainly via the
mevalonic acid (MVA) pathway. The simple isoprenoids (linear
alcohols, diphosphates, etc.) are formed by the successive addition
of C5 units and are classified according to the number of these
terpene units. Polyterpenes are structures containing greater than
40 carbons. Carotenoids are important simple isoprenoids that
function as antioxidants and as precursors of vitamin A. Another
biologically important class of molecules is exemplified by quinones
and hydroquinones, which contain an isoprenoid tail attached to a
quinonoid core of non-isoprenoid origin. Vitamin E and vitamin K, as
well as ubiquinones, are examples of this class.
Saccharolipids
Saccharolipids are compounds in which FAs are linked directly
to a sugar backbone. In saccharolipids, a monosaccharide substitutes
for the glycerol backbone of glycerolipids and glycerophospholipids.
The most familiar saccharolipids in Gram-negative bacteria are the
acylated glucosamine precursors of the Lipid A component of the
lipopolysaccharides (LPS).
Terpenes
Polyketides
Terpenes are lipids with the building blocks of isoprene units

(2-methyl 1,3-butanodiene, CH2=C(CH3)-CH=CH2). Isoprene units
may be linked in a head to tail or in a head to head fashion, and
the resulting compounds can be cyclic or acyclic, and saturated or
unsaturated. Terpenes are classified depending on the number of
isoprene units incorporated into the basic molecular skeleton. Many
terpenes are hydrocarbons, although oxygen-containing compounds
such as alcohols, aldehydes or ketones (terpenoids) are also found.
Moreover, isoprene units are also found within the framework of
certain phenols (quinones) and indole alkaloids. Terpenes are probably
the most widespread group of natural products such as essential
oils, resins, waxes, rubber, carotenoids, etc. They are also involved in
the synthesis of steroids, vitamins, and chlorophyll, as well as in the
acylation of proteins.
Polyketides are synthesized by polymerization of acetyl and

propionyl subunits by classic enzymes as well as iterative and
multimodular enzymes that share mechanistic features with the FA
synthases. They comprise a large number of secondary metabolites
and natural products from animal, plant, bacterial, fungal and marine
sources, and have great structural diversity. Many polyketides are
cyclic molecules whose backbones are often further modified by
glycosylation, methylation, hydroxylation, oxidation, and/or other
processes. Many commonly used anti-microbial, anti-parasitic, and
anti-cancer agents are polyketides or polyketide derivatives, such as
tetracyclines, erythromycins, avermectins, and antitumor epothilones.
Steroids
Steroids are modified triterpenes derived from squalene. They
are lipid compounds based on the fundamental saturated tetracyclic
hydrocarbon 1,2-cyclopentanoperhydrophenanthrene (sterane or
gonane), which can be modified by C-C bond scissions, ring expansions
or contractions, dehydrogenation, and substitutions. Examples of
steroids are estrogen, progesterone, androgens (testosterone and
androsterone), glucocorticoids and mineralocorticoids and they have
biological roles as hormones and signaling molecules.
Sterols are steroid alcohols or steroids with a hydroxyl group in the
3-position of the A-ring. Sterols form part of the cellular membrane
where they influence their fluidity and function and participate in
J Diabetes Metab
Cyanolipids
Cyanolipids are made with FAs esterified to mono- or dihydroxy
nitrile moieties. Cyanolipids are mainly found in cyanobacteria and
plants, and their hydrolysis usually produces Hydrogen cyanide (HCN),
which has a protective effect.
Phenolic lipids
Phenolic lipids are mainly present in plants, fungi, and bacteria.
This heterogeneous group includes simple phenols and polyphenols as
well as their derivatives, and can be classified into coumarins, quinones,
flavonoids and phenolics. They have a wide range of biological effects
including antimicrobials, antioxidants, toxics, enzyme inhibitors, etc.
The single-ring lipid compounds are made up of a catechol, a resorcinol
or a hydroquinone nucleus alkylated by a variable non-isoprenoid
carbon chain.
Page 4 of 17
Lipids containing aminocompounds

These compounds are made of linking FAs with the substances that
contain amino groups. They are classified as (i) aminoalcohols, (ii)
ceramides, (iii) lipoamino acids and lipopeptides and others like (iv)
acyl-CoAs (thioester bond), acyl carnitines (ester bond) and dopamine
(amide bond). Aminoalcohols are long carbon chains containing
one or more alcohol groups and one amino group synthesized by
condensation of an amino acid and an acyl-CoA. Aminoalcohols can
be saturated or unsaturated, linear or branched and can have additional
groups like ethanolamine, choline, and sphingosine. The most common
aminoalcohols are sphingosine and their derivatives. Ceramides are
the simplest sphingolipids that result from the condensation of an
aminoalcohol and a FA through an amide bond (when the condensation
is through an ester bond the result is a wax). Free sphingoceramides
are found in some tissues or are involved as messenger molecules,
although their alcohol function is frequently linked to a glucide
(glycosphingolipids) or is esterified by a phosphoric acid linked to a
polar group (sphingomyelins). Another important group of ceramides
are N-acylethanolamines (NAEs). Lipoamino acids and lipopeptides are
amphipathic membrane lipids composed of one amino acid (lipoamino
acids) or more amino acids (lipopeptides) linked to a FA through an
amide bond. A second FA can be linked to the amino acid through an
ester bond. They may act as virulence factors, or have pharmacological
activity (e.g., lipstatin is a lipase inhibitor used against obesity).
Glycolipids
Glycolipids are complex membrane lipids containing a glycosidic
moiety. They are classified into (i) glycosides of FAs, lipid alcohols and
steroids, (ii) Glyceroglycolipids or glycolipids based on glycerol, (iii)
glycosphingolipids or glycolipids based on ceramides, (iv) Glycosides
of lipoamino acids or lipoamino acids containing glycosyl moieties and
(v) LPS.
Lipids of group (i) are made up of linking a glycosyl moiety (one
or several units) to one or more FAs, fatty alcohols, and alkyl chains.
Lipids of group (ii) consist of a mono-, di-, or oligosaccharide moiety
that via the glycosidic bonds links to the hydroxyl group of glycerol,
which may be acylated (or alkylated) with one or two FAs. Furthermore,
these glycolipids may contain additional groups and chains. They form
compounds such as lipoteichoic acids (LTA) of Gram-positive bacterial
membranes, which consist of polymers of glycerol-1-phosphate linked
to a (phosphatidyl)glycosyl diglyceride., Lipids of group (iii) are a
mono-, di-, or oligosaccharide moiety linked to the hydroxyl group of
a ceramide backbone. The ceramide and the glycosyl group(s), which
can be neutral (unsubstituted) or acidic (substituted with carboxyl,
sulphate or phosphate group(s)), can have further modifications. The
best known ones are cerebrosides (a ceramide linked to a hexose) and
gangliosides (a ceramide linked to an oligosaccharide containing sialic
acid). Lipids of group (iv) including (1) lipids having an amino acid
with N-acyl and/or ester linkages and (2) lipids having a glycerol and an
amino acid with ether linkage. LPS are the endotoxic O-antigens found
in outer membranes of Gram-negative bacteria. The lipid part (Lipid
A) is responsible for the toxic activity of these bacteria and septic shock
and comprises of a backbone of -1,6-glucosaminyl-glucosamine. The
3-position of glucosamine II establishes a glycosidic linkage with a
long-chain polysaccharide. The other hydroxyl and amine groups are
substituted with normal or hydroxy FAs.
Proteolipids
Proteolipids or fatty acylated proteins are proteins that contain one
J Diabetes Metab
or more covalently associated acyl moieties. Proteolipids are divided

into (i) myristoylated proteins in which myristic acid is bound by amide
linkage to glycine residue of the protein and (ii) palmitoylated proteins
in which palmitic acids (or other long FAs) are bound by thioester
linkages to cysteine residues of the protein. Acylation is one of the most
widespread modifications of cytosolic and membrane proteins in all
living things and can direct soluble proteins to membranes.
Biological Functions of Lipids

Fats are one of the main components of the body which are involved
in many different functions. Mainly, they function in the structure of
cell membrane and they are stored in AT in the form of triacylglycerol
(TAG, triacylglyceride or triglyceride) as the source of energy in the
body; hence, they are biologically active molecules.
Membranes
A biological membrane is a form of lipid bilayer in an aqueous
system, in which the polar heads of lipids align towards the polar
aqueous environment, while the hydrophobic tails tend to cluster
together, forming a vesicle, micelles, liposomes, or lipid bilayers
depending on the concentration of the lipid. The glycerophospholipids,
sphingomyelin and sterols (mainly cholesterol) are the main structural
components of biological membranes.
Energy storage
Triglycerides are a major form of energy storage in adipose tissues.
The complete oxidation of FAs provides about 9kcal/g energy that is
higher than that produced from the breakdown of carbohydrates and
proteins (4kcal/g energy).
Signaling
Lipid signaling is a vital part of cell signaling. Lipid signaling
may occur via activation of G protein-coupled receptors (GPCRs)
and members of lipid categories as signaling molecules and cellular
messengers. These include sphingosine-1-phosphate, diacylglycerol
(DAG), phosphatidylinositol phosphates (PIPs), phosphatidylserine,
prostaglandins, steroid hormones such as estrogen, testosterone,
cortisol and oxysterols such as 25-hydroxycholesterol.
Other functions
The fat-soluble vitamins (A, D, E and K), which are isoprenebased lipids, are essential nutrients stored in the liver and adipose
tissues, with a diverse range of functions. Acyl-carnitines are involved
in the transport and metabolism of FAs in and out of mitochondria
during beta oxidation. Polyprenols and their phosphorylated derivatives
also play important roles in transport of oligosaccharides across
membranes. Polyprenol phosphate sugars and polyprenol diphosphate
sugars function in extracytoplasmic glycosylation reactions, in
extracellular polysaccharide biosynthesis (for instance, peptidoglycan
polymerization in bacteria), and in eukaryotic protein N-glycosylation.
Cardiolipins are a subclass of glycerophospholipids containing four acyl
chains and three glycerol groups that are particularly abundant in the
inner mitochondrial membrane. They are believed to activate enzymes
of oxidative phosphorylation reaction.
Fats and their Importance in the Pathogenesis of

Metabolic Disorders
Fats and carbohydrates are the energetic molecules of the body.
This point highlights the metabolic functionality of these molecules in
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the body. However, lipids and carbohydrates have different biophysical
properties; therefore, they influence the metabolic system of the body
in different ways. Lipids are insoluble particles in the watery based
circulation that require transporters for transfer. Transporters are
soluble particles such as vesicles, endoplasmic reticulum (ER), the
Golgi apparatus, intracellular lipid droplets and intra-circulatory
lipoproteins [4,5]. These particles are made from lipids and proteins
that influence the function of the particles; therefore, each particle has
different biological functions in the body R. However, carbohydrates
are soluble crystal molecules that do not need carriers for transport.
Both the carbohydrates and lipids influence blood viscosity, which
has a significant effect on pathological events [6-8]. The change of
viscosity affects cytoskeleton function and movement of intracellular
organelles [9] and as an environmental factor changes gene expression
pattern of cells [10-12]. Furthermore, viscosity has a shear stress
effect in the circulation and together with constituents of the lipid
particles influences the cardiocerebrovascular function [7]. During
atherosclerosis, the environmental hyperviscosity could enhance
atherothrombosis via influence on the membrane stretch [13].
With regard to biochemistry, lipids have almost double energy
than carbohydrates and are considered as the energy storage molecules
in the form of TAG in adipose tissues. Therefore, the main function
of adipose tissue is the lipid storage capacity and not the catabolic
function. Storage of energy in the form of TAG in adipose tissues is the
best way for energy reservation in comparison with glycogen storage
in the skeletal muscles and liver because of three reasons. Firstly, fats
produce 9.3 Kcal/gram energy, while this amount for carbohydrates
is 4 kcal/gram. Secondly, lipid storage in adipose tissues requires less
water than carbohydrate storage in the form of glycogen. Therefore,
compared to the glycogen storage in skeletal muscle and liver the weight
of adipose tissues is less than the amount of energy which is reserved
in it [14]. Finally, the body cannot use the energy of lipids directly in
the metabolic pathways. For this purpose, lipids should be degraded to
acetyl-CoA, which is the intermediate molecule of glucose oxidation
process, to be used in the mitochondrial oxidative phosphorylation
(OXPHOS) reaction and release their energy. Therefore, there is a close
interaction between lipid and carbohydrate pathways in cells. On the
one hand, excess of carbohydrates in the body is reserved in the form
of neutral lipids such as cholesterol esters, TAG or FA. In shortage of
available energy in the form of carbohydrate, lipolysis is increased via FA
oxidation (FAO) to produce acetyl-CoA to be used in the carbohydrate
pathways. This capacity of the body, which is nutritional storage in the
form of lipids in the feeding state for usage in the form of carbohydrates
in the starvation state, is one of the fundamental capacities of living
things and is essential for life.
Lipid storage in the body happens normally in the white adipose
tissue (WAT). Therefore, structurally the main cytoplasmic organelles
of WAT-adipocytes consist of a nucleus and a (in mature adipocyte)
or lots of (in small adipocytes) functional lipid organelles for
sequestration of extracellular lipids (Figure 3) [14]. The number and
activity of mitochondria in this tissue is not high. These lipid organelles
that are also called lipid droplets (LDs) have almost the same structural
properties as lipoproteins (Figure 4). They have an external layer
of phospholipids that covers the intra-organelle TAGs. LDs exist in
different organs, namely skeletal muscle, liver and pancreas; however,
in adipose tissue they are highly specialized for lipid storage [14].
Carbohydrates are the energetic molecules that the body directly
consumes in starvation and because of their solubility and availability
have a strong influence on the metabolic system of the body. The
J Diabetes Metab
Figure 3: The structure of adipose tissue

Adipose tissue is composed of some cells including adipocytes, fibroblasts,
endothelial cells, macrophages and stem cells. Adipocyte is the main cell of
adipose tissue that is mainly composed of a nucleus and a large lipid droplet
surrounded by a cytoplasmic membrane. The structure of a lipid droplet is
similar to lipoproteins.
Figure 4: Comparison between structural similarity between lipoproteins and

adipocytes-LDs
Both the lipoprotein particles and adipocytes-LDs compose of external bilayer
lipid components (phospholipids) that cover the central TAG component of
particles. Apolipoproteins are assembled in the phospholipid layer and are
unique among these particles.
required energy of the body is produced either directly via degradation

of carbohydrates or indirectly via NADH2 and FADH2 oxidation during
the OXPHOS reaction. Therefore, functional mitochondria are one of
the fundamental parameters in proper cellular metabolism, mainly in
the catabolic tissues such as hepatocytes and myocytes. Skeletal muscles,
which require a huge amount of energy for movement, have highly
functional mitochondria. In expert athletes, LDs of the skeletal muscles
that are in close contact with mitochondria are expanded to store a high
level of intramuscular triglyceride (IMTG). Athletes muscle cells have
high insulin sensitivity that could be because of this close functional
proximity between the mitochondria and the LDs as well as the high
ability of their LDs for intracellular-lipid sequestration [14]. In contrast,
during physiological obesity the concentration of glucose and free FAs
(FFAs) in circulation and consequently the metabolic functionality of
metabolic tissues will increase to storage the excess energy level of the
body in the form of triacylglycerol in their LDs. This leads to increase
in the function of mitochondria for OXPHOS reaction of the energetic
compounds of acetyl-CoA (product of both lipid and carbohydrate
degradation). In the pathological obesity state, mitochondrial
dysfunction lead to FAO reduction, lipotoxicity in the cytoplasm, ER
Page 6 of 17
stress and metabolic disorders [15-18]. In mitochondrial dysfunction,
the amount of heat increases. Heat generation happens due to the high
amount of ATP production following OXPHOS reaction as well as the
leaky membrane of the inner mitochondrial membrane (IMM) during
ATP production. In obese adults, the mass and function of the brown
adipose tissue (BAT) are strongly low. Activated BAT could have a great
effect in alleviation of the metabolic disorders during obesity [19].
BAT increases energy expenditure and weight loss and improves lipid
and glucose homeostasis. Therefore, active BAT is able to uptake large
quantities of lipid and glucose from the circulation [20]. Moreover, each
ATP produces 8 kcal energy that is 20% of its total energy and the rest
of the energy is wasted as heat to maintain body temperature. In obesity
state, there is also defect in LD degradation and TAG lipolysis due to
the low level of adipose triglyceride lipase (ATGL) gene expression
in skeletal muscles [21,22]. This matter increases the level of their
bioactive lipid species such as diglyceride (or diacylglycerol, DAG) and
ceramides that is known as lipotoxicity [22]. TAG accumulation in
glycolytic muscles can induce FA-induced insulin pathway disturbance
or FA-induced insulin pathway disturbance (FAID) [14].
Origin of Fats and Lipid Uptakes

Fats originate from the external (TAG, cholesterol and
phospholipids of food) and internal parts of the body (TAG and
cholesterol storages of adipose tissues and lipoproteins). In the external
origin, lipid solubilization (or emulsification) in the intestine happens
by lipophilic bile acids, which are synthesized from cholesterol in the
liver. This process renders fats accessible to the lipases. Fat digestion
starts from the stomach by gastric lipase, which is active and stable
in acidic environments [23]. The main part of lipid degradation takes
place in the small intestine and via steapsin or pancreatic lipase and
pancreatic phospholipase A2 (PLA2). These lipases affect TAGs, which
are produced via esterification of 3 FAs with the carbon backbone
of glycerol. Fifty percent of TAG degradation happens by pancreatic
lipases that separate sequentially the acyl root (or FA) of the two outer
positions (1 and 2) of the glycerol carbon groups of TAGs and
produce monoglyceride. PLA2 is able to split off the FA of the middle
position () of the glycerol carbon group of monoglycerides and release
glycerol in 40% of TAG degradation. Ten percent of the TAGs can be
directly absorbed from the intestine cells to the circulation.
There are different hormones in the small intestine that can
affect fats. These hormones are (i) secretin and gastrin that stimulate
secretion of pancreatic electrolytes, (ii) pancreozymin that stimulates
the secretion of pancreatic lipase to degrade lipids and TAGs and (iii)
cholecystokinin that causes contraction of gall bladder for entrance of
bile salts in the duodenum.
Monoglycerides, following absorption in the intestinal enterocytes,
are assembled again to produce TAGs. Heavy lipids such as LCFAs,
TAGs, monoglyceride, DAGs, phospholipids and cholesterols enter the
bloodstream via the lymphatic vessels. Short-chain FAs directly enter
the circulation and form a complex with albumin and enter the liver via
the portal vein [24].
In intestinal cells, lipids are used for chylomicron (CM) assembly
and are then released to the lymphatic vessels and circulation.
Chylomicrons (CMs) have a hydrophilic external layer and a
hydrophobic internal layer. In the endothelial cells of tissues, they
become degraded via lipoprotein lipase (LPL) and their FAs enter the
liver cytoplasm for FAO.
Retour of External Cholesterol in the Body

Most of the external cholesterol is in the form of free cholesterol,
J Diabetes Metab
which is the form that can be absorbed by the enterocytes. Therefore,

esterified cholesterol loses its FA using cholesterol esterase and is
converted to the free form. Inside the enterocytes, the free cholesterol
becomes esterified again and are assembled together to form CMs,
which enter the bloodstream via lymphatic vessels. In circulation,
CMs are degraded by LPL and the esterified cholesterol enters the liver
via the portal vein and converts to free cholesterol. Eighty percent of
cholesterol in the liver is stored in the gallbladder in the form of bile
salts and 20% is used for generation of other cholesterol-based products
like sex hormones, phospholipids, CMs, cell membrane lipids, and
vitamin D3. Cholesterol is released from the gallbladder to the intestine
and is again absorbed via enterocytes.
Lipoproteins
The aqueous environment of the body poses problems with the
transport of the hydrophobic substances between organs. Hence,
animals have evolved plasma lipoproteins that facilitate transport of
TAGs and cholesterol between the liver, adipose compartment and
tissues [25]. Originally these structures were not thought to be of major
importance for transmitting endocrinologically relevant signals, but
this view is now changing. In 2006, Panakova et al. [26] showed that
lipophorin (the Drosophila equivalent of VLDL) carried hydrophobic
ligands activating Wnt signaling and hedgehog morphogen pathways
and these effects were physiologically highly relevant in the model
organism, whereas Queiroz et al. have shown that the morphogen
is carried by lipoproteins in humans as well [27-29]. Interestingly, it
has been recently reported that vitamin D resides in LDL and that
this is relevant for modulating signaling in atherosclerotic plaques
[30,31]. Apart from hydrophobic morphogenes, other hydrophobic
signaling molecules may also reside in lipoproteins. Many hormones
are highly hydrophobic and evidence is available that lipoproteins may
be involved in their efficient transport through the body. In ApoE-/mice for instance, both endocannabinoid [32] and glucocorticoid [33]
signaling is disturbed and is strongly associated with inflammation,
insulin unresponsiveness and hepatic steatosis, suggesting that
endocannabinoid carrying by lipoproteins is a relevant process. Thus
the lipoprotein compartment may have an underestimated role in the
human endocrinology.
Lipoprotein constituents
Lipoproteins are biochemical transporters that are composed of
proteins and lipids. The main function of lipoproteins in the body is
transport of lipids through the circulation from the sources of lipids
such as the intestine and liver to other tissues that require these fats
as their energy suppliers or use them as structural materials in their
membrane. Their structure consists of an amphipathic monolayer of
lipids, which is composed of an assembly of hydrophilic head groups
of phospholipids and free (non-esterified) cholesterol together with
apolipoproteins that face the aqueous phase and cover the intra
hydrophobic (non-polar) part of their structure which are TAGs
and cholesterol esters [34]. The polarity of the surface lipoproteins
prevents their aggregation and allows them to be solubilized in the
circulation [35]. Lipids of the lipoproteins are TAG, free cholesterol,
cholesterol esters, and phospholipids like phosphatidylcholine (PC),
phosphatidylethanolamine (PE), phosphatidylinositol (PI), and
sphingomyelin (SM) [25]. The particle proteins, via their interactions
with each other and also with other proteins including enzymes and the
cell surface proteins, determine whether the lipids should be absorbed
from or exported to particular tissues. The overall metabolism and
structure of lipoproteins is determined by apolipoproteins and also the
interactions with the peripheral receptor molecules [36,37]. The main
Page 7 of 17
Another nomenclature, which is used for explanation of the
lipoprotein metabolism pathway, based on the origin of their lipid, is
exogenous and endogenous lipoprotein pathways. In the exogenous
lipoprotein pathway, the lipid components of the lipoproteins
are synthesized by the intestine from dietary lipids, while in the
endogenous lipoprotein pathway the lipid components are synthesized
by the liver [40]. In the exogenous pathway, the intestinal lipids
(TAGs, phospholipids, cholesterol) are absorbed by the epithelium
and assembled with apoB48, apoA-I, apoA-II and apoA-IV to make
the nascent chylomicron (nCM), which is secreted to the lymphatic
vessels (via its apolipoproteins) and released directly (bypass liver) to
the circulation via the subclavian vein. In the circulation, HDL delivers
its apolipoproteins (apoC-II and apoE) to the nCM to make mature
chylomicron (mCM). These exchangeable apolipoproteins protect the
TAG-rich lipoprotein particles (CM and VLDL) from non-specified
interaction with the plasma and lead to their correct configuration for
the action of LPL. In the skeletal muscle and AT, mature chylomicron,
via activation of the endothelial LPL in the presence of phospholipids
and its cofactor apoC-II, ensures the hydrolysis of TAG to glycerol and
FAs to be consumed or stored by tissues. Glycerol is returned to the
liver and kidney to be converted to the glycolytic intermediates and
the phospholipid and apoA and apoC of mCM is transferred to HDL.
The hydrolyzed chylomicron, known as remnant chylomicron (rCM),
contains cholesterol esters, apoE and apoB48. rCM is transferred
to the liver through the circulation, which in turn rCM ends up
with endocytosis mediated by the interaction of apoE with the rCM
receptors in the hepatocytes [38,41-44]. Ultimately, rCM is degraded in
lysosome, which results in release of FAs and glycerol [41].
Figure 5: Comparison between the structures of lipoproteins
There is a reverse correlation between the size and density of lipoproteins
that represent the percentage of the lipids and proteins in these particles. For
instance, HDL has the highest density (and protein percentage) and conversely
the lowest size (and lipid percentage).
categorization of lipoproteins is based on their diameter and density as

well as their proteins and lipids compositions. Based on the density,
which results from the percentage of the proteins and lipids in their
structure, they are mainly divided into five major classes including
high-density lipoprotein (HDL), low-density lipoprotein (LDL),
intermediate-density lipoproteins (IDL), very low-density lipoprotein
(VLDL) and CMs [38]. The density of lipoproteins is associated
with the percentage of their protein. In contrast, there is an inverse
association between the size of a lipoprotein and its density. HDL is the
smallest lipoprotein and has more density with the highest percentage
of proteins (Figure 5).
Metabolism of lipoproteins and atherosclerosis

LDL poses pathological challenges relating to atherosclerotic
plaque formation through the distribution of cholesterol from the liver
to the tissues and especially the endothelium [27]. Conversely, HDL is
involved in the transport of lipids from tissues and back to the liver or
excretion from the body, a process called reverse cholesterol transport
(RCT) [39]. Thus, HDL has an anti-atherogenic and protective effect
in the body. Chylomicrons and VLDL are involved in the transport
of TAGs. Chylomicrons transport the newly absorbed TAGs from the
intestine to the skeletal muscle for consumption, to the adipose tissue
for storage or to the liver for synthesis of VLDL. VLDL is secreted
from the liver to the circulation for transport to other tissues including
adipose tissue.
J Diabetes Metab
In the endogenous pathway, liver is the main source of VLDL lipid

constituent. The assembly of intracellular TAG and cholesterol in the
liver is maintained by apoB100 and delivered to the circulation by
lipid transporters [40,45]. Similar to CMs, circulating HDL provides
apoE and apoC-II to VLDL [46,47]. VLDLs contain TAG, cholesterol,
cholesteryl ester, apoB-100, apoC-I, apoC-II, apoC-III and apoE. Thus,
VLDL plays an important role in the delivery of FFA to the AT to
store energy as inactive fuel in the form of TAGs in the adipocytesassociated LDs or supply active energy for skeletal muscles and other
tissues via FFA delivery [45]. LPL ensures release of FAs and glycerol
via hydrolyzation of TAGs and loss of apoCs from VLDL to transfer
back to HDL. The VLDL is then converted to remnant VLDL or IDL,
which contains apoB-100 and apoE and is an interplayer between
VLDL and LDL [38]. The released energy components in the form of
glycerol and FAs are used by the skeletal muscles and adipocytes. As
in CMs, the interaction of rVLDL or IDL with LDL receptors of the
liver in the presence of apoB-100 and apoE ends in TAG hydrolyzation
and loss of apoE to constitute the rIDL or LDL lipoproteins. ApoE is
transferred back to HDL. Therefore, the predominant apolipoprotein of
LDL is apoB-100. Lack of apoE in LDL decreases the affinity of LDL to
its cognate receptors of the liver. Fusion of endosomes with lysosomes
leads to degradation of apolipoproteins and hydrolyzation of cholesterol
esters to free cholesterols, which is incorporated into the plasma
membranes. Excess intracellular cholesterol enhances the activity of
acyl-CoA: cholesterol acyltransferase (ACAT) for re-esterification of
cholesterol to the cholesterol esters for intracellular storage.
Many studies have shown that hypertriglyceridemia (with
VLDL as TAG carrier) similar to hypercholesterolemia (with LDL as
cholesterol transporter) is directly linked to the risk of cardiovascular
morbidity and mortality and atherosclerosis [48]. Atherosclerosis is an
inflammatory disease that is triggered by oxidation of LDL cholesterol
(LDL-C), which in turn the oxidized LDLs (ox-LDLs) are trapped in
Page 8 of 17
the extracellular matrix of the sub-endothelial space [49]. The ox-LDL
is absorbed by the tissue macrophages to form foam cells (macrophages
loaded with lipids) and promote inflammatory gene expression (e.g.,
nuclear factor kappa B (NFkB) pathway) that initiate the inflammatory
response. Inflammation primes the formation of fatty streak and in
turn the arterial calcification [50,51]. This is the starting point for
the aggregation of coagulation cells that express different coagulation
factors for initiation and maintenance of a coagulation state for a short
period and tissue repair that is followed by stimulation of the fibrinolysis
pathway for ending and removing this process [52]. ApoD via its
influence on lipid metabolism affects the process of atherosclerosis and
ageing [53,54].
HDL with its anti-inflammatory, antioxidant and vasodilatory
properties is considered as the atheroprotective particle. These effects
are a result of the role of HDL in RCT. HDL is synthesized in the liver
and small intestine with the property that it is devoid of any cholesterol
and cholesteryl esters and contains apoA-I, apoC-I, apoC-II and apoE
and enzymes including glutathione peroxidase 1 (GPx), paraoxonase 1
(PON1), platelet activating factor acetylhydrolase (PAF-AH, also called
lipoprotein-associated phospholipase A2, Lp-PLA2), lecithin: cholesterol
acyltransferase (LCAT), cholesterol ester transfer protein (CETP) and
sphingosine-1-phosphate (S1P). GPx, PON1 and PAF-AH have
antioxidant activities. HDLs, via apoA-I and the action of ATP binding
cassette transporter A1 (ABCA1), interact with macrophages in the
subendothelial space of the tissues to transfer cholesterol from the
macrophages and form pre- HDL. The free cholesterol, through
interaction with apoA-I, is then esterified by LCAT and internalized
into the hydrophobic core of the pre- HDL particle and enlarged to
HDL2 and HDL3.
VLDL and converting their TAGs to non-esterified FAs (NEFA) and

2-monoacylglycerol [17,56,57]. They also increase the cellular uptake
of rCM, cholesterol rich lipoproteins and FFAs. The apolipoproteins
of lipoprotein particles have a role in targeting of the lipoproteins to
the tissues and also functions as a cofactor (especially apoC-II) for LPL
although apoC-III is an inhibitor of LPL activity [58,59]. Apart from its
enzymatic function, LPL has an important role in lipid metabolism and
transport. LPL also acts simultaneously as a linker between lipoproteins
and cell surface receptors, including proteoglycans such as cell surface
related LDL receptors and heparan sulfate proteoglycans (HSPG) and
thus facilitates the uptake of lipoproteins by the tissues [59]. In the
literature, malfunctioning of LPL has been associated with a plethora
of pathological conditions including atherosclerosis, obesity, diabetes,
chylomicronemia, Alzheimer disease, and cachexia [60,61].
Expression of LPL is mediated through a complex interaction
between sterol regulatory element-binding protein (SREBP), cytokines,
LPS [60], peroxisome proliferator-activated receptor-alpha (PPAR),
cyclic adenosine 3,5-monophosphate (cAMP) response element
binding protein (CREBP) and activator protein-1-like factors [60,62,63].
In addition, expression of LPL is enhanced by the differentiation
of macrophage and adipocyte and is under the influence of specific
nutritional factors, blood glucose levels, FAs, and the levels of hormones
such as insulin, catecholamine and thyroid, growth hormone, estrogen,
prolactin, parathyroid hormone, retinoic acid and vitamin D3 [60].
LPL is produced in the parenchymal cells of adipocytes, heart, skeletal
muscles as well as macrophages and is distributed along the vascular
mesh [60]. Thereafter, it is secreted and translocated to the functional
heparan sulphate proteoglycan (HSPG)-binding site on the luminal
surface of the endothelium and hydrolyzes lipoproteins [64].
HDL transfers its cholesterol esters to VLDL and LDL via the activity
of CETP and its RCT property. In this situation TAG is transferred
from VLDL to HDL. Ultimately, conversion of VLDL to LDL transfers
these cholesterol esters to the hepatocyte via LDL receptors. However,
some of the LDLs are oxidized in the peripheral tissues and induce
atherosclerosis. Furthermore, TAG-rich HDL is targeted by hepatic
lipase and becomes smaller and unstable and loses its apoA-I. In the
absence of apoA-I, HDL is not able to act as RCT. One approach for
increasing the circulatory level of HDL is inhibition of CETP. CETP
blockage reduces cholesterol transfer to VLDL and LDL and the level of
ox-LDL and also decreases the level of TAG-rich HDLs [55].
The level of LPL production in adipose tissue and the skeletal

muscle determines whether dietary lipids are mainly stored in the
adipose tissue (to induce obesity) or are used for energy consumption
in the skeletal muscle (to induce weight loss). Thus, the control of LPL
production is important for understanding obesity and pathological
weight loss [65,66]. During fed state, the activity of enzymes is more
in the adipose tissue than the skeletal muscle to store the extra energy,
while exercise leads to a higher level of enzyme activity in the skeletal
muscle [45,67]. Therefore, expression of LPL by adipose tissue and
skeletal muscle is often considered to constitute an anti-atherogenic
influence, while the expression of LPL by the endothelial cells and
macrophages has a pro-atherogenic effect. In this way, import of LDL
to macrophages and foam cell formation in the subendothelial space
is the main trigger of atherosclerosis pathogenesis. Insulin is the main
regulator of the LPL activity in adipose tissue. During fed state, insulin
upregulates LPL expression and consequently FA storage in adipose
tissue. However, in fasting state, the level of insulin is low and LPL
expression is increased in the skeletal muscle that leads to absorption
of fats by the skeletal muscles. Moreover, insulin unresponsiveness is
associated with a proinflammatory state of adipose tissue in which
production of cytokines such as TNF and IL-6 reduces LPL expression
in adipose tissue [45]. This leads to hypertriglyceridaemia and
susceptibility to coronary artery disease. Cytokine-induced inhibition
of LPL expression in adipose tissue is also the pathophysiology of
cachexia in cancers [67]. Thus, it is expected that anti-geriatric factors,
if they exist, should also influence LPL activity.
Lipoprotein Lipase (LPL)
Fatty Acid Oxidation (FAO)
These pancreatic, hepatic, and endothelial lipases are soluble

hydrolytic enzymes whose main function lies in the hydrolysis of TAGs
of the circulatory TAG-rich lipoprotein particles, namely CMs and
FA beta oxidation (FAO) is a mitochondrial (and peroxisomal for

LCFAs) process in which the conserved energy of the FAs is released in a
stepwise manner. FAs are long carbon chain molecules that during FAO
HDL also, via extraction of the free cholesterol from cell membrane,
decreases the intracellular esterified cholesterol, which is mobilized
to the membrane to replace the membrane cholesterol. This process
happens via the action of ATP-binding cassette protein G1 (ABCG1).
HDL moves to the liver to bind the scavenger receptors class B type
I (SR-BI) and release its cholesterol esters to the hepatocytes through
caveolae; however, it is not absorbed to the hepatocytes.
HDL has a different effect on vascular biology. In normal state, the
apoA-I, GPx, PON1 and PAF-AH of HDL have antioxidant properties;
whereas in the inflammatory state, these properties become inactivated
and HDL becomes proatherogenic. Besides, modification of apoA-I by
myeloperoxidase, which is produced from the atherosclerotic plaques,
tends to lower affinity of HDL for interaction with macrophage and
removal of cholesterol from foam cells.
J Diabetes Metab
Page 9 of 17
beta-hydroxyacyl-CoA. This product becomes oxidized by using
dehydrogenase and NAD+ coenzyme to produce beta ketoacyl-CoA.
Beta ketoacyl-CoA is degraded to acetyl-CoA and acyl-CoA molecule
with 2 carbons less than the first acyl-CoA molecule by using betaketothiolase (or acetyl-CoA acyl transferase) and one molecule CoASH. This acyl-CoA is dehydrogenated again to start the second cycle
of the process to lose two extra carbons. This process continues till the
long chain of FA becomes completely degraded to acetyl-CoA [68].
Energy balance in FAO

In the Krebs cycle, degradation of each acetyl-CoA produces 12
ATP molecules. Each propionyl-CoA produces 6 ATP that is yielded
from 1 GTP, 1 FADH2 (equal to 2 ATP) and 1 NADH2 (equal to 3 ATP).
Furthermore, conversion of propionyl-CoA to succinyl-CoA requires
1 ATP. Therefore, each propionyl-CoA at the end produces 5 ATP. In
addition, in each cycle of beta oxidation, which leads to degradation
of one acetyl-CoA from the LCFAs, 1 FADH2 (equal to 2 ATP) and 1
NADH2 (equal to 3 ATP) are produced. The number of cycles for each
molecule of FA is calculated by subtracting one from the number of the
final products. Moreover, at the level of thiokinase reaction 1 ATP is
consumed that should be considered in the final calculation.
Examples
1. How many ATP molecules are produced from a 6-carbon FA?
Figure 6: Fatty acid beta-oxidation (FAO)

The cytoplasmic FAO reaction is a multistage process in which LCFAs are
degraded to the multiple two carbon glycolysis intermediate (acetyl-CoA) as
well as one three carbon component (propionyl-CoA) in the FAs that contain
an odd number of carbon atoms. In this catabolic reaction, the reduced
components of the OXPHOS reaction (NADH2, FADH2) are produced.
and in each step, 2 carbon molecules of FA are degraded to produce

the activated 2-carbone (2c-) intermediate, acetyl-CoA. In addition,
reduction of NADH+ and FADH+ cofactors produces NADH2 and
FADH2 during FAO. Degradation of FAs with odd number of carbons
(produced in some bacteria) produces one molecule propionyl-CoA
and one molecule acetyl-CoA instead of two molecules acetyl-CoA
in the last step. Propionyl-CoA converts to methylmalonyl-CoA and
succinyl-CoA to enter the Krebs cycle (Figure 6).
Oxidation of FAs happens in two stages in the cytoplasm and in
the mitochondria. In the cytoplasmic stage, FAs are first activated
via conversion to acyl-CoA by using fatty acyl-CoA synthase (or
thiokinase), Mg2+ as cofactor, coenzyme A (CoA-SH) and ATP.
Thereafter, acyl-CoA, by using acyl-carnitine palmitoyltransferase
transferase I (CPT-I), forms a complex with carnitine (or betahydroxy-gamma-trimethylammonium butyrate) in order to pass
the mitochondrial membrane. Carnitine is produced from the lysine
amino acid in the liver and kidney cells. Therefore, any problem in the
metabolism of lysine leads to disturbance in the formation of carnitine
and consequently FA metabolism and storage of TAGs in cells. In acylCoA with long chain hydrocarbons, acylcarnitine translocase enzyme
transfers the acylcarnitine across the IMM.
In the mitochondrial stage, acyl-CoA via acyl-carnitine transferase
II, becomes separated from acyl-carnitine. Subsequently, acyl-CoA
becomes dehydrogenated by using acyl-CoA dehydrogenase (a
flavoprotein) and flavin adenine dinucleotide (FAD) coenzyme to
produce dehydroacy-CoA (or enoyl-CoA). Dehydroacyl-CoA becomes
hydroxylated by using hydratase and one molecule water to produce
J Diabetes Metab
First stage: Calculation of the number of products (including

2C-Acetyl-CoA and 3C-propionyl-CoA) that is yielded from each
molecule of 6C-FA. Each 6C-FA produces three 2C-Acetyl-CoA
molecules, which produces 36 ATP molecules.
Second stage: Calculation of the number of cycles that is used for
complete degradation of 6C-FA. The total number of cycles is equal to the
total number of products (acetyl-CoA in the odd-numbered FAs) that
is yielded at the end of the degradation (3 acetyl-CoA molecules in this
example) minus one. As in each cycle 5 ATP is produced, via OXPHOS
reaction of 1 NADH2 and 1 FADH2, therefore, during degradation of
each 6C-FA in two cycles totally 10 ATP molecules are produced.
Third stage: Consideration of the consumption of one ATP molecule
by thiokinase.
This amount is used just one time; therefore, it should be considered
at the end of the calculation.
Final calculation: 36 ATP + 10 ATP - 1 ATP = 45 ATP
2. How many ATP molecules are produced from a 17-carbon FA?
First stage: Each 17C-FA produces 7 2C-acetyl-CoA molecules,
which is equal to 84 ATP molecules as well as one 3C-propionyl-CoA
that produce 5 ATP molecules.
Second stage: Total number of cycles that is used for total
degradation of 17C-FA is 7. This amount is calculated by consideration
of the total number of products (8 molecules in this example) minus
one. The total amount of energy production in each cycle is equal to 35
ATP molecules.
Third stage: Consideration of the consumption of one ATP
molecule by thiokinase
Final calculation: 84 ATP + 5 ATP + 35 ATP - 1 ATP = 123 ATP
molecules
Regulation of FAO
The level of acetyl-CoA is one of the main determinant parameters in
Page 10 of 17
the regulation of FAO. Acetyl-CoA is the product of glucose degradation
during glycolysis and pyruvate dehydrogenase (PDH) reaction as well
as FAO. Therefore, acetyl-CoA is the main linker molecule between the
carbohydrate and lipid pathways. Acetyl-CoA is consumed in different
pathways including (i) the Krebs cycle, (ii) gluconeogenesis using
pyruvate carboxylase (PC), (iii) oxaloacetate production by using CO2
to store glucose in the liver as glycogen, (iv) FA biosynthesis and (v)
cholesterol synthesis [69]. One of the parameters that influence the
concentration of acetyl-CoA in the body is hormones. In physiological
states, insulin is secreted from the pancreatic beta cells following feeding.
Insulin is an antilipolytic hormone and the inhibitor of FAO [70]. This
means that in excess of energy level in the body carbohydrate catabolism
proceeds to lipid storage. In diabetic states, insulin unresponsiveness
decreases the level of lipogenesis. This leads to lipolysis and elevation
of the level of FFAs in circulation. FFAs are sedimented to non-adipose
tissues such as skeletal muscle and liver to enhance FAID in these organs
[14]. In type 1 diabetic state and shortage of insulin, FAO and acetylCoA production in the body is increased. Acetyl-CoA is the substrate of
3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA), which is the substrate
of HMG-CoA lyase in the ketone bodies pathway.
Fatty Acid Synthesis

FA synthesis starts when the concentration of acetyl-CoA
in cytoplasm is high. This cytoplasmic process happens via the
enzymatic activity of a single, homodimeric, multifunctional protein,
the FA synthase (FAS) complex. Each FAS monomer contains three
catalytic N-terminal domains including beta-ketoacyl-ACP synthase
(KS), malonyl/acetyl transferase (MAT) and dehydrase (DH) and
four C-terminal domains including enoyl-ACP reductase (ER),
beta-ketoacyl-ACP reductase (KR), acyl carrier protein (ACP) and
thiosterase (TE) that are separated from each other by a structural
core. The conserved ACP (central protein) acts as the mobile domain
responsible for shuttling the intermediate fatty acid substrates to various
catalytic sites. Coenzyme A is the source of the phosphopantetheine
prosthetic group of the ACP domain, which contains thiol (central SH).
One of the peripheral enzymes (KS) also contains thiol (peripheral SH),
which belongs to the cysteine amino acid [71].
During FA synthesis, acetyl-CoA is carboxylated to malonylCoA in cytosol by using acetyl-CoA carboxylase (ACC), ATP, CO2
and biotin as coenzyme. Thereafter, malonyl transacylase and acetyl
transacylase separate CoA-SH from malonyl-CoA and acetyl-CoA
roots and join malonyl roots to the ACP domain (central SH) and
acetyl roots to the active site of cysteine thiol of the KS domain
(peripheral SH). Subsequently, one molecule CO2 is released from the
malonyl root using carboxylase and the acetyl root joins to the rest of
the molecule on the central SH to produce acetoacyl-ACP. AcetoacylACP becomes reduced using reductase and NADPH2 as coenzyme
and produces -hydroxyacyl-ACP. Thereafter, dehydrase separates one
H2O to produce -dehydroacyl-ACP (or enoyl-ACP), which is reduced
by using -dehydroacyl-ACP reductase and NADPH2 to produce
butyryl-ACP (4C-acyl-ACP). Consequently, the butyryl root is again
transferred from the central thiol to the peripheral thiol and the central
thiol becomes free again for joining to a new malonyl root (Figure 7).
The final product of this cycle is palmitoyl-ACP (a 16C-FA).
Palmitoyl-ACP is released from the enzymatic complex using deacylase
and one molecule water to produce palmitate. Mitochondria and
microsomes produce FAs with longer chains or with unsaturated bonds
[72,73]. Insulin is a lipogenic hormone that stimulates synthesis of both
the FAs and cholesterol with the regulation of SREBP-1c and SREBP-2
in each pathway respectively [74].
J Diabetes Metab
Figure 7: Fatty acid synthesis

This cytoplasmic anabolic reaction happens when the concentration of acetylCoA (the intermediate of glucose degradation pathway) is high. This means
that in high consumption of carbohydrates and excess amount of energy in the
body, some part of acetyl-CoA is converted to FAs for storage in the form of
TAG. Insulin, that is the main hormone of pancreatic beta cells and is released
during feeding state, stimulates this process. NADPH2 cofactor (product of the
pentose phosphate pathway) is required in this process.
ACC is the main regulatory enzyme of FA synthesis that is regulated

in three different ways including (i) allosteric reaction of the local
metabolites, (ii) hormones and (iii) phosphorylation. Allosterically,
palmitoyl-CoA, a LCFA, is the inhibitor and citric acid is the stimulator
of ACC [75]. Excess of acetyl-CoA, through stimulation of the Krebs
cycle and citrate synthesis, is converted to malonyl-CoA and stored as
FAs [76]. Malonyl-CoA inhibits transport of FAs to the mitochondria
for FAO [77]. Phosphorylation of ACC by 5 AMP-activated protein
kinase (AMPK) decreases the level of malonyl-CoA and inhibits FA
synthesis [76]. AMPK is activated when the intracellular energy is
low. AMPK also stimulates FAO by augmenting the inhibitory effect
of malonyl-CoA for transport of FA to the mitochondria. In low level
of glucose (e.g., in type 1 diabetes), stimulation of cAMP/PKA (protein
kinase A) pathway by glucagon and epinephrine [78] inhibits AMPK;
therefore, acetyl-CoA is consumed in ketogenesis pathway instead of
FA synthesis [79]. Ketone bodies are the other energy source of the
body in situations in which the level of glucose in the body is low. In
high glucose level, insulin stimulates the pentose phosphate pathway
[80] as well as ACC and FA synthesis [81]. Upstream regulatory factors
(USFs) and SREBP-1 transcription factors mediate this process [82].
Polyunsaturated FA in the liver [83] and leptin in adipocyte inhibit
expression of SREBP [84].
Triacylglyceride (TAG) Synthesis

Esterification of three FA molecules with glycerol produces TAGs.
TAGs are the main lipid components of LDs and are stored in adipose
tissues, skeletal muscles, liver, lungs and intestine to provide energy for
the metabolic processes. In adipose tissue, there is a balance between
degradation and synthesis of fats in normal state.
Page 11 of 17
The first step of TAG synthesis is consumption of glycerol in the
form of glycerol-3-phosphate (G3P). G3P is produced in two different
ways in the liver and adipose tissue. In the liver, G3P is made by
phosphorylation of glycerol using glycerol kinase and ATP. Glycerol is
derived from degradation of adipocyte-TAGs and is transferred to the
liver via circulation. In adipose tissue, synthesis of G3P via the liver
pathway does not happen due to the lack of glycerokinase; however,
G3P is made from reduction of dihydroxyacetone phosphate (DHAP,
glycolysis metabolites) by glycerol-3-phosphate dehydrogenase
(G3PDH).
In the next step, two molecules of acyl-CoA (FAs) join to G3P
using phosphatidic synthetase or fatty-acyl-CoA transferase to make
phosphatidic acid. Phosphatidic acid, using phosphatase, loses one
phosphate group and produces DAG. DAG, using TAG synthase,
combines with one extra acyl-CoA and produces TAG (Figure 8). TAG
is then transported to VLDL of the liver as well as the adipocytes-LDs
[85]. Glycerol can also follow gluconeogenesis to produce glucose and
glycogen [69].
TAG Degradation
TAGs are sequentially hydrolyzed by the activity of desnutrin/ATGL,
hormone-sensitive lipase (HSL) and MAG lipase (MAGL) to produce
FAs and glycerol [86-88]. The liberated FAs are used in different ways
including (i) as the source of energy at the time of energy deprivation,
(ii) for re-esterification in AT, (iii) for beta oxidation in other tissues and
(iv) for storage as phospholipids or other lipid types. Dysregulation of
hormones such as insulin and androgens during stress (e.g., fasting) or
metabolic system disorders such as obesity-induced metabolic syndrome
and lipodystrophy affects the function of lipolytic enzymes in adipose
tissue. Under fasting state, the level of the catecholamines increases
in adipose tissue due to absorption by circulation or by sympathetic
innervations. Catecholamines increase the adenylate cyclase activity and

intracellular cAMP concentration and PKA activity and consequently
phosphorylation and stimulation of hydrolytic activity of HSL, which is
translocated to the adipocytes-LDs for TAG breakdown. Glucocorticoids,
via stimulation of the desnutrin/ATGL enzymes, can also stimulate
lipolysis [87]. In fed state, insulin inhibits lipolysis by dephosphorylation
of HSL and activation of phosphodiesterase (PDE) that decreases the
level of cAMP. Insulin, via phosphoinositide-3-kinase/AKT (PI3K/AKT)
pathway, phosphorylates and inhibits PDE3B which has an inhibitory
effect on the cAMP activity. Another inhibitory effect of insulin on
lipolysis is through phosphoprotein phosphatase-1 (PP1) and its negative
regulation on HSL [87].
Other pathways for phosphorylation of HSL are via cGMP
dependent kinase [89] and calcium-induced protein kinase C/
mitogen-activated protein kinases / extracellular-signal-regulated
kinase (PKC/MAPK/ERK) activity [90,91] that activate HSL. AMPK
inactivates HSL lipolytic properties and has a competitive effect with
PKA in HSL phosphorylation and activity [17,92]. Another regulator
of HSL activity is perilipin A that associates with LD and enhances
HSL lipolytic activity [92,93]. In basal states, perilipin A maintains a
low rate of lipolysis in the LDs; however, under hormone stimulation,
PKA-mediated perilipin phosphorylation through facilitating the
HSL translocation to the LDs or its interaction with HSL, stimulates
HSL activity. HSL has an effect on broad substrates of lipid molecules
including TAG, DAG, MAG, retinyl and cholesteryl esters, but it mostly
affects DAG and cholesteryl ester [94].
Desnutrin/ATGL contains a patatin-like domain that hydrolyzes
TAG and does not hydrolyze cholesteryl and retinyl esters [86].
Desnutrin expression is limited to adipose tissue and is overexpressed
in adipocyte differentiation and glucocorticoid stimulation and is
downregulated during feeding and insulin stimulation [88]. Other
parameters that are important in lipolysis are thyroid hormone, growth
hormones [95], natriuretic peptide, alpha-melanocyte stimulating
hormone (-MSH) and TNF that stimulate lipolysis [96,97]. Adenosine
[98] and neuropeptide Y [99] inhibit lipolysis and prostaglandins such
as PGE2 and PGI2 have a bipolar effect.
Hormones and Triglyceride Metabolism Regulation

Insulin has an antilipolytic effect and beta-adrenergic hormones
have a stimulatory effect on TAG degradation. Another protein for
regulation of TAG is lipin-1. It also has an effect on mitochondrial
oxidation, development of mature adipocytes, storage and utilization
of glucose and FAs of peripheral tissues [100,101]. They interact
with some gluconeogenic nuclear receptors such as PGC-1, PPAR,
glucocorticoid receptor (GR) and hepatocyte nuclear factor-4-alpha
(HNF4) [102]. During the acute phase of inflammation, LPS and
proinflammatory cytokines negatively regulate lipin1 in adipose tissue
and therefore the level of FFAs and VLDL is increased in circulation
[101]. Both adrenaline and contraction-mediated events mediate TAG
hydrolysis by HSL [103]. These events deactivate AMPK secretion
and activate PKC/ERK and cAMP/PKA pathways that are activated
by muscle contraction-induced intracellular calcium release and
epinephrine stimulation that lead to PKC and ERK activation and
stimulation of HSL [17,104].
Figure 8: Triacylglycerol (TAG) biosynthesis
Esterification of glycerol with three FAs produces TAG. This anabolic
cytoplasmic pathway happens mostly in the liver and AT. Liver TAGs are
transferred to adipose tissue using VLDL and the TAGs of AT is reserved in the
adipocytes- LDs to be used at the time of starvation.
J Diabetes Metab
Adenylyl cyclase has an important role in lipid metabolism.

Adenylyl cyclase, via influence on ATP and conversion to cAMP,
activates protein kinase using one ATP molecule. Activated PKA
phosphorylates and activates TAG lipase [104]. Glycerol and FA, which
are produced from TAG, are transferred to the liver via circulation.
Page 12 of 17
Hormones through influence on adenylyl cyclase are able to
regulate lipid metabolism. Epinephrine (adrenaline), norepinephrine
(noradrenaline) [105], glucagon [106,107], adrenocorticotropic
hormone (ACTH) [108], hydrocortisone [109], thyroxine [110],
serotonin [111] and thyroid-stimulating hormone (TSH) [112]
influence adipocytes directly and stimulate adenylyl cyclase and
lipolysis [113]. Conversely, insulin has a negative regulatory effect
on adenylyl cyclase and hence inhibits lipolysis. Therefore, insulin
is an antilipolytic or lipogenesis agent; however, the antilipolytic
effect of insulin is independent of this effect [114]. Insulin inhibits
lipolysis mainly via activation of PDE, which catalyzes the conversion
of cAMP to 5/ AMP [115]. Insulin functions in different ways to
inhibit lipolysis including (i) stimulation of entrance of glucose to
cells and glycolysis that increases DHAP concentration (substrate of
FA synthesis), (ii) activation of FAS (enzyme of FA synthesis), (iii)
inhibition of TAG degradation via inhibition of HSL, (iv) activation
of glycogen synthase to convert G3P to glycogen and (v) activation of
glucose-6-phosphate (G6P) dehydrogenase (G6PDH) that stimulates
the pentose phosphate pathway and produces NADPH2 (cofactor for
FA synthesis). In this stage also the concentration of DHAP increases
and is reduced via G3PDH and produces G3P (substrates of TAG
synthesis).
Ketone Bodies
Ketone bodies are acetone (C-CO-C), acetoacetic acid (C-CO-CCOOH) and beta hydroxyl butyric acid (C-COH-C-COOH). Normally,
the concentration of these products in the circulation is low (1 mg/dl);
however, in type 1 diabetes, anesthesia and prolonged fasting their
concentration increases and leads to ketosis and metabolic acidosis.
When the concentration of ketone bodies in the serum exceeds the
threshold absorption by the kidney tubules, it is released in the urine
(ketonuria). In normal states, the concentration of ketone bodies is not
detectable in the urine. Ketone bodies are produced in the liver, testes
and ovaries [116], and are transported to the brain and cardiac muscles
for consumption as energy source via conversion to acetyl-CoA (Figure
9).
Synthesis of ketone bodies

In this cytoplasmic reaction, 2 acetyl-CoA produce acetoacetylCoA using beta-ketothiolase. Acetoacetyl-CoA produces HMG-CoA
using HMG-CoA synthase and acetyl-CoA. HMG-CoA loses one
acetyl-CoA using HMG-CoA lyase and produces acetoacetic acid,
which follows two pathways; (i) it becomes reduced and produces beta
hydroxyl butyric acid using beta hydroxyl butyric acid dehydrogenase
and NAD+ or (ii) it loses one CO2 and produces ketone using
acetoacetate decarboxylase.
Degradation of ketone bodies

In order to use ketone bodies as energy source, the body only
uses acetoacetic acid. Acetone evaporates quickly and is discharged
via ventilation and hydroxyl butyric acid is converted to acetoacetic
acid. During degradation, acetoacetic acid is converted to acetoacetic
acid-CoA via thiokinase and using CoA-SH and ATP. Thereafter,
acetoacetic acid-CoA combines with one CoA-SH and produces two
acetyl-CoA molecules using beta ketothiolase. In skeletal muscles,
the first stage of ketone bodies degradation occurs in different
ways. In skeletal muscles, succinyl-CoA (instead of ATP) is used for
combination of CoA-SH to acetoacetic acid; therefore, totally 23 ATP
are produced in skeletal muscles, while this amount in other cells is 24
ATP. Degradation of acetoacetyl-CoA to two acetyl-CoA molecules
J Diabetes Metab
Figure 9: Ketone bodies synthesis

Ketone bodies are the product of HMG-CoA, which is produced from assembly
of three acetyl-CoA. During type 1 diabetes, shortage of insulin production
by pancreatic beta cells stimulates intracellular FAO and the concentration of
acetyl-CoA, which is used for Ketone bodies production. Ketone bodies are
one of the energy sources of cells.
produces 24 ATP because each acetyl-CoA produces 12 ATP during

the Krebs cycle.
Regulation of ketone body synthesis

During fasting, TAG-adipocyte is degraded to release its energy.
Over-supply of TAG in the liver induces synthesis of ketone bodies.
This event happens when the ratio of insulin / glucagon is decreased in
fasting state. Therefore, in high level of glucagon, ACC is inhibited and
consequently FAO is stimulated. In FAO, fatty acyl-CoA is converted to
acetyl-CoA to be used in the Krebs cycle for energy production. In this
state, NADH2 / NAD+ ratio increases. In high level of this ratio and when
enough energy supply of the hepatocytes is prepared, the extra acetylCoA is consumed in the ketogenesis pathway. Moreover, oxaloacetate
is converted to malate to generate glucose via gluconeogenesis. In the
chronic fasting state, gene expression of mitochondrial HMG-CoA
synthase is stimulated that induces the ketogenesis pathway.
Cholesterol Biosynthesis
Cholesterol is one of the main fat components of the body that has
both external (foods like egg, meat and milk) and internal sources.
Inside the body cholesterol is made from acetyl-CoA in hepatocytes,
enterocytes, testes and ovaries [117] and contains less than 60% of the
total proportion of cholesterol in the blood. Acetyl-CoA is yielded from
oxidation of glucose and FAs.
In the cytoplasmic process of cholesterol biosynthesis 3 acetyl-CoA
are joined to each other to produce HMG-CoA. HMG-CoA can either
follow cholesterol production by the function of HMG-CoA reductase
or enter the ketogenesis pathway. NADPH2 is the cofactor of this process
that is produced from the pentose phosphate pathway (Figure 10).
Regulation of cholesterol synthesis

Cholesterol synthesis is regulated through the enzymes of this
pathway. These are 3-hydroxy-3-methyl-glutaryl-CoA reductase
(HMG-CoAR) and acyl-CoA: cholesterol acyltransferase (ACAT),
for regulation of intracellular free cholesterol as well as LDL receptormediated uptake and HDL-mediated reverse transport that regulate
Page 13 of 17
genes are cholesterol synthesis enzymes (HMG-CoA synthase, HMGCoA reductase, farnesyl diphosphate synthase and squalene synthase),
FA synthesis enzymes (ACC, FAS, stearoyl-CoA desaturase (SCD)) and
TAG synthesis enzyme (G3P acyltransferase (GPAT)) and also for lipid
uptake (e.g., LDL receptor) [122]. The concentration of cholesterol in ER
determines the regulation of gene expression in cholesterol synthesis.
The synthetic sterol, through a negative feedback loop, inhibits the
cleavage of SREBP and synthesis of additional sterol
SREBP is in three isoforms of SREBP-1a (involved in both the FA
and cholesterol synthesis), SREBP-1c (involved in FA synthesis) and
SREBP-2 (involved in cholesterol synthesis and LDL receptor gene
expression). The inactive precursor of SREBP is bound to the ER
membrane. The three TM proteins of ER membrane (SREBP2, SCAP and
Insig) and the two cleavage proteins (S1P and S2P) regulate formation
of SREBP. SREBP precursor protein is a 2TM-protein that belongs to
the basic helixloophelix (bHLH)-Zip family of transcription factors
and contains one cytosolic C terminal SCAP binding domain and one
cytosolic N terminal SREBP domain that mediates the dimerization,
nuclear entry and DNA binding to sterol regulatory element (SRE)
segment to enhance the genes encoding for biosynthesis of lipids. The
cholesterol-sensing protein, SREBP cleavage activating protein (SCAP),
is an 8TM-protein containing SSD domain similar to HMG-CoAR. Its
cytosolic domain binds to the cytosolic C terminal domain of SREBP
protein. High level of sterol forms a complex with 6TM-Insig and SCAP
and induces binding of the SSD of SCAP with the Insig protein. The
Insig protein always stays in the ER membrane that leads to retention of
SREBP-SCAP precursor complex in the ER and its inactivation.
Figure 10: Cholesterol synthesis

Excess amount of energy (or high concentration of acetyl-CoA) in the cell
is stored as lipid. Cholesterol synthesis happens in liver and adipose tissue
cytoplasm following consumption of ATP and NADPH2.
the plasma cholesterol level. HMG-CoAR is the key rate limiting

sterol synthetic enzyme that has 8 transmembrane (8TM) spans and
is anchored to the ER membrane. It is regulated by the level of cellular
cholesterol. High level of cholesterol has a negative feedback effect
on HMG-CoAR and its gene expression. In addition, cholesterol
stimulates HMG-CoAR polyubiquitination and degradation which is
modulated by its transmembrane (TM) sterol-sensing domain (SSD)
and its role in proteasome degradation. HMG-CoAR is also regulated
by phosphorylation and dephosphorylation. Phosphorylation of HMGCoAR inhibits its function. HMG-CoAR phosphorylation happens
either via activated AMPK [118] or activated protein phosphatase
inhibitor-1 (PPI-1). The phosphorylated forms of AMPK and PPI1 are active. Activated PPI-1 inhibits HMG-CoAR phosphatase
(also called PP2A), which dephosphorylates (and activates) HMGCoAR. Activated PPI-1 also inhibits PP2C, which dephosphorylates
(and inactivates) AMPK. Inactivated HMG-CoAR phosphatase and
phosphorylated AMPK maintain HMG-CoAR in the phosphorylated
and inactivated states [119]. Glucagon and epinephrine decrease
cholesterol synthesis through activation of the inhibitor of PPI-1, while
insulin dephosphorylates and activates HMG-CoAR [120].
SREBP is the master regulator of lipid homeostasis [121] and a
transcription factor that enhances lipogenesis in adipose tissue by
controlling the gene expression of enzymes of lipid synthesis. These
J Diabetes Metab
In low concentration of sterol, the complex does not interact with the
Insig protein. Conformational change in SCAP leads to SREBP-SCAP
complex translocation to the Golgi apparatus using COPll vesicles.
Subsequently, two separate site-specific proteolytic cleavages by S1P and
S2P proteins happen that release the membrane-bound SREBP to the
cytoplasm. The released SREBP2 translocates to the nucleus to function
as transcription factor for upregulation of cholesterol synthesis genes
including HMG-CoAR. After a short period, SREBP is ubiquitinated
and degraded to become inactive (Figure 11).
Figure 11: Illustration of the role of SREBP in lipid production induction

The ER membrane bound SREBP transcription factor is in an inactive form.
It makes a complex with SCAP and together anchor to Insig protein of ER
membrane. In high concentration of sterol this anchored junction is released
and the SREBP-SCAP complex is transferred to the Golgi apparatus.
Degradation of SREBP and release of its bHLH domain to the nucleus induces
the process of lipid production.
Page 14 of 17
Conclusion
Lipid-carbohydrate interaction is one of the fundamental
parameters in regulation of the energy metabolic system. Disturbance
in the function of the adipose tissue as the main fat storage organ of
the body leads to FAID and consequently metabolic disorders. In this
review, the biochemical pathways of the main energetic molecule of
the body (lipids) are summarized in such a way that researchers can
follow the association between these pathways easily. Understanding
these biochemical pathways will help biologists to comprehend the
pathophysiology of metabolic diseases properly.
Nomenclatures
Acetyl group, methyloxidocarbon or ethanoyl group is the organic
group of acetic acid (C-CO-OH). Acetyl group is the acyl with the
chemical formula C-CO-. The acetyl group contains a methyl group
single bonded to a carbonyl. The acetyl moiety is a component of many
organic compounds such as acetyl-CoA, acetylcysteine, acetylcholine,
acetaminophen (or paracetamol) and acetylsalicylic acid (or aspirin).
Acyl group is an alkyl group attached to a carbon-oxygen double
bond (R-CO-). Acylation is the substitution of an acyl group into
something. The simplest acyl group is ethanoyl group (C-CO-).
Ethanoyl chloride is made by joining a chloride atom with an ethanoyl
group (C-CO-Cl).
Aldehyde is an organic compound with the structure R-CHO
consisting of a carbonyl center (CO) bonded to hydrogen and an R
group, which is any generic alkyl or side chain. In aldehydes, carbonyl
is located at the end of a carbon skeleton, while in ketones carbonyl is
placed between two carbon atoms.
Aldehyde group or formyl group is the aldehyde group without R
(-CHO).
Aliphatic molecules are basically non-cyclic or cyclic molecules
that are not aromatic. Thus, instead of the normal benzene ring that has
3 double bonds inside, it is just a saturated closed ring.
Amphipathic molecules are molecules that contain both polar
(hydrophilic) and non-polar (hydrophobic) regions.
Alkane is an acyclic structure of saturated hydrocarbon that
consists of only hydrogen and carbon that join together with single
bonds. Their general chemical formula is CnH2n+2. Each carbon atom is
able to bind to four hydrogen or carbon atoms and each hydrogen atom
can join to one carbon atom. Carbon skeleton or carbon backbone is a
series of linked carbon atoms that are joined together. The size of the
alkane depends on the number of carbons that makes the molecule. The
simplest alkane is methane (CH4).
Alkoxy group is an alkyl group singular bonded to oxygen (R-O).
The simplest alkoxy groups are methoxy (R-O-C) and ethoxy group
(R-O-C-C).
(R-O-aryl). An alkoxy or aryloxy group bonded to an alkyl or aryl (R1O-R2) is ether. If bonded to H it is an alcohol. An alkoxide (RO) is the
ionic or salt form; it is a derivative of an alcohol where the proton has
been replaced by a metal, typically sodium.
Carbonyl group is a functional group composed of a carbon atom
double-bonded to an oxygen atom (C=O). This structure is found in
different compounds including Aldehyde (R-CO-H), ketone (R1-COR2), carboxylic acid (R-CO-OH), ester (R1-CO-OR2), amide (R1-CONR2R3), enone (R1-CO-C R2=C R3R4), acyl halide (R-CO-X) in which
X represents the halide, acid anhydride (R1-CO-O-CO- R2) and imide
(R1-CO-N R2-CO- R3)
Carboxyl group (or carboxy) is a functional group consisting of a
carbonyl (C=O) and a hydroxyl (OH) group, which has the formula
-CO-OH or COOH.
Carboxylic acid is an organic acid in which at least one carboxyl
group is present. Its general formula is R-COOH, where R is some
monovalent functional group. The simplest examples of these groups
are formic acid (H-COOH) and acetic acid (C-COOH). Acids with two
or more carboxyl groups are called dicarboxylic, tricarboxylic, etc. The
simplest dicarboxylic example is oxalic acid (COOH)2, which is just two
connected carboxyls. Other important natural examples are citric acid.
Salts and esters of carboxylic acids are called carboxylates.
Esters are chemical compounds consisting of a carbonyl (CO)
adjacent to an ether linkage (C-O-C). They are formed from the
reaction of an oxoacid (like carboxylic acid) with a hydroxyl compound
such as an organic alcohol or phenol. For instance, triglycerides are the
FA esters of glycerol. Esters are usually derived from an inorganic acid
or organic acid in which at least one -OH (hydroxyl) group is replaced
by an -O-alkyl (alkoxy) group, and most commonly from carboxylic
acids and alcohols. That is, esters are formed by condensing an acid
with an alcohol.
Ethers are organic compounds that contain an ether group.
Ether group is an oxygen atom connected to two alkyl or aryl groups
(R1-O-R2) such as in anesthetic diethyl ether, (CH3-CH2-O-CH2-CH3).
Isoprene or 2-methyl-1,3-butadiene group is one of the common
building blocks of the lipid structures with the formula C=C(C)C=C.
Ketoacyl group is the other building block of the lipid structure
that consists of two alkane groups (R) binding to carboxyl group (CO).
Methyl group is a hydrocarbon group that is an alkyl derived from
methane, containing one carbon atom bonded to three hydrogen atoms
(CH3-).
Oxoacids are acids that (i) contain oxygen (ii) contain at least one
other element, (iii) have at least one hydrogen atom bound to oxygen
(iv) form an ion by the loss of one or more protons.
Acknowledgement
Alkyl is an alkane missing one hydrogen atom. An acyclic alkyl

has the general formula CnH2n+1. The smallest alkyl group is methyl
(CH3-). An alkyl group is symbolically abbreviated with R. A cycloalkyl
is generated by removal of a hydrogen atom from a cycloalkane and
formation of a ring with the general formula CnH2n-1.
I would like to express my ultimate appreciation to Dr. Nessa Dashty

Rahmatabady for her useful comments in this paper.
Aryl group is the substituent derived from an aromatic ring, be it

phenyl, naphthyl, thienyl, indolyl, etc. A simple aryl group is phenyl,
C6H5; it is derived from benzene.
2. Boelsma E, Hendriks HF, Roza L (2001) Nutritional skin care: health effects of
micronutrients and fatty acids. Am J Clin Nutr 73: 853-864.
Aryloxy groups have an aryl group singular bonded to oxygen

J Diabetes Metab
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Dashty, J Diabetes Metab 2014, 5:1

Diabetes & Metabolism

A Quick Look at Biochemistry: Lipid Metabolism

Keywords: Lipid; Carbohydrate; Lipoprotein; Atherosclerosis

Lipid Categorization and their Definitions

*Corresponding author: Monireh Dashty, Department of Cell Biology, University

Volume 5 Issue 1 1000324

Volume 5 Issue 1 1000324

developmental signaling as secondary messengers. The most important

Terpenes are lipids with the building blocks of isoprene units

Polyketides are synthesized by polymerization of acetyl and

Volume 5 Issue 1 1000324

Lipids containing aminocompounds

or more covalently associated acyl moieties. Proteolipids are divided

Biological Functions of Lipids

Fats and their Importance in the Pathogenesis of

Volume 5 Issue 1 1000324

Figure 3: The structure of adipose tissue

Figure 4: Comparison between structural similarity between lipoproteins and

required energy of the body is produced either directly via degradation

Volume 5 Issue 1 1000324

Origin of Fats and Lipid Uptakes

Retour of External Cholesterol in the Body

which is the form that can be absorbed by the enterocytes. Therefore,

Volume 5 Issue 1 1000324

categorization of lipoproteins is based on their diameter and density as

Metabolism of lipoproteins and atherosclerosis

In the endogenous pathway, liver is the main source of VLDL lipid

Volume 5 Issue 1 1000324

VLDL and converting their TAGs to non-esterified FAs (NEFA) and

The level of LPL production in adipose tissue and the skeletal

Lipoprotein Lipase (LPL)

Fatty Acid Oxidation (FAO)

These pancreatic, hepatic, and endothelial lipases are soluble

FA beta oxidation (FAO) is a mitochondrial (and peroxisomal for

Volume 5 Issue 1 1000324

Energy balance in FAO

Figure 6: Fatty acid beta-oxidation (FAO)

and in each step, 2 carbon molecules of FA are degraded to produce

First stage: Calculation of the number of products (including

Volume 5 Issue 1 1000324

Fatty Acid Synthesis

Figure 7: Fatty acid synthesis

ACC is the main regulatory enzyme of FA synthesis that is regulated

Triacylglyceride (TAG) Synthesis

Volume 5 Issue 1 1000324

innervations. Catecholamines increase the adenylate cyclase activity and

Hormones and Triglyceride Metabolism Regulation

Adenylyl cyclase has an important role in lipid metabolism.

Volume 5 Issue 1 1000324

Synthesis of ketone bodies

Degradation of ketone bodies

Figure 9: Ketone bodies synthesis

produces 24 ATP because each acetyl-CoA produces 12 ATP during

Regulation of ketone body synthesis

Regulation of cholesterol synthesis

Volume 5 Issue 1 1000324

Figure 10: Cholesterol synthesis

the plasma cholesterol level. HMG-CoAR is the key rate limiting

Figure 11: Illustration of the role of SREBP in lipid production induction

Volume 5 Issue 1 1000324

Alkyl is an alkane missing one hydrogen atom. An acyclic alkyl