TEM-976; No.
of Pages 8
Review
Thyroid hormone regulation of hepatic
lipid and carbohydrate metabolism
Rohit A. Sinha1*, Brijesh K. Singh1*, and Paul M. Yen1,2
1
Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169547,
Singapore
2
Sarah W. Stedman Nutrition and Metabolism Center, Departments of Medicine and Pharmacology and Cancer Biology,
Duke University Medical Center, Durham, NC 27705, USA
Thyroid hormone (TH) has important roles in regulating
hepatic lipid, cholesterol, and glucose metabolism. Re-
cent findings suggest that clinical conditions such as
non-alcoholic fatty liver disease and type 2 diabetes
mellitus, which are associated with dysregulated hepat-
ic metabolism, may involve altered intracellular TH ac-
tion. In addition, TH has key roles in lipophagy in lipid
metabolism, mitochondrial quality control, and the reg-
ulation of metabolic genes. In this review, we discuss
recent findings regarding the functions of TH in hepatic
metabolism, the relationship between TH and metabolic
disorders, and the potential therapeutic use of thyromi-
metics to treat metabolic dysfunction in the liver.
Thyroid hormone and metabolic homeostasis
Thyroid hormone (TH, see Glossary) mediates important
physiological processes such as development, growth, and
metabolism [1,2]. Intracellular triiodothyronine (T3) is the
active form of TH and binds to the thyroid hormone recep-
tor (TR), which is a transcription factor that belongs to the
nuclear receptor superfamily (Figure 1). The TR exists in
two isoforms: TRa and TRb. The TRa isoform is highly
expressed in the heart, muscle, and adipose tissue, where-
as TRb is the predominant isoform in the liver [3]. The TR
acts as a ligand-dependent transcription factor to regulate
genes involved in the biological functions of TH (Figure 1)
[4].
TH has profound effects on body weight, thermogenesis,
and lipolysis; these effects are mediated primarily through
the action of TH on skeletal muscle and adipose tissue [1].
TH can also regulate fatty acid (FA), cholesterol, and
carbohydrate homeostasis through its actions on the liver
(Figure 2) [1]. Thus, thyroid dysfunctions can result in
intrahepatic as well as systemic dysregulation of the me-
tabolism of nutrients that serve as important energy
sources for cells and adversely affect hepatic lipid and
carbohydrate metabolism [1].
In clinical hypothyroidism, patients gain weight owing to
a decreased basal metabolic rate, particularly in muscle and
brown fat [1]. Additionally, hypothyroidism is associated
Corresponding author: Yen, P.M. (paul.yen@duke-nus.edu.sg).
Keywords: thyroid hormone; lipid metabolism; glucose metabolism; liver.
*
Sinha, R.A. and Singh, B.K. contributed equally to this review
1043-2760/
2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tem.2014.07.001
with non-alcoholic fatty liver disease (NAFLD) [5], a condi-
tion that is estimated to occur in more than 30% of American
adults, many of whom also have obesity and/or type 2
diabetes mellitus (T2DM) [6]. Hypothyroidism is also con-
sidered a risk factor for developing NAFLD because hypo-
thyroid patients have an increased prevalence of NAFLD
[5,7], and both hypothyroidism and NAFLD are associated
with hyperlipidemia, obesity, and insulin resistance. In
support of their mutual effects, studies have shown that
Glossary
Carbohydrate metabolism: refers to the production, storage, and use of
carbohydrates in cells to maintain energy homeostasis. It is highly conserved
and is essentially glucose metabolism to control blood glucose levels.
De novo lipogenesis: the process in which acetyl-CoA is converted to FAs,
which are then esterified with glycerol to form TGs that are packaged in VLDLs
and secreted from the liver.
Gluconeogenesis: during starvation, glucose is generated from non-carbohy-
drate carbon substrates (such as pyruvate, lactate, and FAs) in the liver to
maintain blood glucose levels.
Hyperlipidemia: a medical condition characterized by abnormally high levels of
lipid or lipoproteins in the blood.
Hyperthyroidism: a condition in which the thyroid gland produces and secretes
excessive amounts of the free thyroid hormones T3 and/or T4. Graves disease
is the most common cause of hyperthyroidism.
Hypothyroidism: a common endocrine disorder of underactive thyroid or low
thyroid, in which the thyroid gland does not produce enough thyroid hormone.
It causes several symptoms including tiredness, cold intolerance, and weight
gain.
Lipid metabolism: refers to the regulation of lipids in cells such as their
degradation (lipolysis) or formation (lipogenesis). TGs and cholesterol are the
major components of lipid metabolism. TGs are important for energy storage
in adipocytes and muscle cells, whereas cholesterol is a ubiquitous constituent
of cell membranes, steroids, bile acids, and as signaling molecules.
Lipolysis: a highly regulated process of lipid breakdown that involves the
hydrolysis of TGs into glycerol and FAs.
Lipophagy: the autophagic degradation of cellular lipids, which involves the
sequestration of lipid droplets and their degradation via lysosomal lipase.
Non-alcoholic fatty liver disease (NAFLD): a condition in which fat accumulates
in the liver independent of alcohol intake. It is generally related to metabolic
disorders and is one of the major causes for fatty liver. Non-alcoholic
steatohepatitis is the most extreme form of NAFLD and a major cause of liver
cirrhosis.
Nuclear receptor superfamily: a family of transcription factors, most of which
directly bind to DNA in a hormone-dependent manner to regulate gene
expression.
b-Oxidation: a multi-step process of FA breakdown to form acetyl-CoA in the
mitochondrial matrix, which subsequently enters into the tricarboxylic acid
cycle.
Reverse cholesterol transport (RCT): a process resulting in the net movement
of cholesterol from peripheral tissues back to the liver via the plasma
compartment.
Thyroid hormone (TH): includes thyroxin (T4) and triiodothyronine (T3). T3 is a
ligand for TRs, which modulate cell proliferation, development, and metabo-
lism. TH is produced by the thyroid gland.
Trends in Endocrinology and Metabolism xx (2014) 18 1
TEM-976; No. of Pages 8

Review Trends in Endocrinology and Metabolism xxx xxxx, Vol. xxx, No. x

T4 T3
S
(i) ACC1, LPOT14, FAS
XR, C ,
Lipogenesis hREB
P (iii)) mediated
TRE +
, ME
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GF
Lipolysis
ysis

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Cytoplasm TH transporters ((Lipophagy,
agy,
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ene
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T4 T3 T2 -Oxidaon e CD Ala
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T3 synthesis +

T3
T3
HATs TRENDS in Endocrinology & Metabolism
Histone Gene
CoAct
+ T3 RXR TR
T3 acetylaon
Figure 2. Thyroid hormone regulation of fatty acid, cholesterol, and glucose
TRE
Transcriponal acvaon metabolism. (i) Thyroid hormone (T3) may increase fatty acid (FA) uptake in the
Nucleus liver via the regulation of FA transporter proteins such as FA translocase (FAT; also
HDACs Histone known as CD36). T3 is known to increase hepatic lipogenesis by upregulating
NCoR
T3 RXR TR
deacetylaon
proteins including Spot14, FA synthase (FAS), acetyl-CoA carboxylase 1 (ACC1),
TRE G
Gene liver X receptor (LXR), carbohydrate-responsive element-binding protein
(CHREBP), and malic enzyme (ME). Activation of hepatic lipases and lipophagy
Transcriponal repression
has been implicated in the intrahepatic lipolysis induced by T3. FAs released via
lipolysis are shuttled into hepatic mitochondria for oxidation; this process is
positively regulated via the T3 induction of carnitine palmitoyltransferase-1 (CPT-
1), sirtuin 1 (SirT1), peroxisome proliferator-activated receptor gamma, coactivator
TRENDS in Endocrinology & Metabolism
1 alpha (PGC1a) and fibroblast growth factor-21 (FGF-21). (ii) Cholesterol uptake
via low-density lipoprotein receptor (LDL-R) endocytosis is promoted by T3. Other
Figure 1. Thyroid hormone signaling. Thyroxine (T4), the precursor of 3,5,30 -
proteins involved in cholesterol uptake, such as sterol regulatory element-binding
triiodothyronine (T3), or T3 enters the cytoplasm via various thyroid hormone (TH)
protein-1c (SREBP-2) and scavenger receptor class B1 (SR-B1), are also induced by
transporters (e.g., MCT8, MCT10, and OATP1C1). The activation and inactivation of
T3. Key genes involved in cholesterol turnover and bile production, such as
TH occur through iodothyronine deiodinases (Dio1, Dio2, and Dio3), which constitute
cytochrome P450 7A1 (Cyp7A1; also known as cholesterol 7-alpha-
a subfamily of deiodinase enzymes. Dio1 and Dio2 convert prohormone thyroxine
monooxygenase) and ATP-binding cassette sub-family G member 8 (ABCG5/8),
(T4) to the active hormone triiodothyronine (T3). Inactivation of TH occurs through
are also induced by T3 to increase net reverse cholesterol transport. (iii) T3 bound
Dio3, which converts T4 to the inactive reverse triiodothyronine (rT3) or converts
thyroid receptor (TR) directly upregulate TR target genes and key gluconeogenic
active T3 to the inactive diiodothyronine (T2). Active T3 enters the nucleus and binds
enzymes such as phosphoenolpyruvate carboxykinase 1 (PCK1) and glucose-6-
to TH receptors (TRs), resulting in the recruitment of co-activator complexes (Co-Act)
phosphatase (G6PC) in the liver. Increased deacetylation and activation of the
with histone acetyl transferase (HAT) activity. The HAT activity of Co-Act increases
master gluconeogenic transcription factor forkhead box O1 (FoxO1) by SirT1 is
acetylation of histone protein tails, thus creating a permissive chromatin
also modulated by T3 to increase gluconeogenesis. Apart from regulating
environment, near TREs on the target gene, and promoting gene transcription. T3
gluconeogenic gene transcription, increased alanine transport and inhibition of
trans-activates the expression of genes in nearly every vertebrate cell. TRs, in the
insulin signaling may also contribute to TH-induced hepatic glucose production. +
absence of T3, recruit nuclear co-repressor complexes (NCo-R) with histone
indicates positively regulated.
deacetylase activity (HDAC), which ultimately repress target gene transcription.
Abbreviations: RXR, retinoid X receptor; TRE, thyroid hormone response element;
MCT8, monocarboxylate transporter 8; MCT10, monocarboxylate transporter 10;
OATP1C1, organic anion-transporting polypeptide 1c1.

key target genes of TH are downregulated in fatty livers of
morbidly obese patients undergoing bariatric surgery [8].
Hypothyroid patients also commonly have hypercholes-
terolemia due to decreased hepatic low-density lipoprotein
receptor (LDL-R) expression, which leads to an im-
pairment in cholesterol uptake [9]. This, in turn, leads
to a decrease in cholesterol turnover and excretion, and a
marked increase in serum apolipoprotein B (ApoB) [10],
total cholesterol, and LDL cholesterol levels. A decrease in
the clearance of triglycerides (TGs) from plasma and an
accumulation of intermediate LDL particles has also been
observed in hypothyroid patients [10].
In hyperthyroidism, the basal metabolic rate of patients
is increased and often accompanied by weight loss when
caloric intake cannot keep pace with increased energy
consumption [11]. However, serum total cholesterol and
TG levels are decreased owing to increased clearance via
the reverse cholesterol transport (RCT) pathway and he-
patic b-oxidation is increased due to lipolysis from adipose
2
tissue [11]. In the hyperthyroid state, excessive hepatic
lipid oxidation and oxidative phosphorylation can generate
reactive oxygen species that cause hepatic tissue damage
[12]. Indeed, hepatitis and liver failure have been reported
to occur in uncontrolled and/or prolonged hyperthyroidism
[13]. Additionally, hyperthyroidism can induce gluconeo-
genesis and glycogenolysis. It is a well-known clinical
phenomenon that hyperthyroidism can induce hyperglyce-
mia as well as worsen glycemic control in diabetic patients
[14].
With the advent of new molecular biological methods,
knockout and knock-in mouse models, and metabolic char-
acterization of different physiological and genetic states,
we are beginning to gain a much deeper understanding of
TH actions on liver metabolism. In this review, we describe
the molecular and intracellular mechanisms utilized
by TH that impact the hepatic regulation of lipids and
carbohydrates in normal and pathological conditions.
These findings not only enhance our understanding of liver
TEM-976; No. of Pages 8
Review
dysfunction associated with metabolic syndrome, but may
also provide new tools for the diagnoses and treatment of
NAFLD and related disorders.
TH regulation of hepatic FA uptake
Circulating free FAs (FFAs) generated through the lipoly-
sis of adipose TG stores are an important source of lipid for
the liver. FFAs are taken up by hepatocytes via protein
transporters such as fatty acid transporter proteins
(FATPs), liver FA binding proteins (L-FABPs), and FA
translocase (FAT; also known as CD36). Studies have
shown that knockdown of FATP2 and FATP5 protected
against high fat diet-induced hepatosteatosis. Knock down
of FATP5 also partitioned lipids towards skeletal muscle
and heart, and away from the liver [15]. Similarly, upre-
gulation of FAT in the livers of lean mice increased hepatic
FA uptake, TG storage, and secretion. [16]. Additionally,
L-FABP knockout mice were resistant to diet-induced
hepatic TG accumulation [17,18]. Although FA transpor-
ters are transcriptionally induced by peroxisome prolifera-
tor-activated receptors (PPARs) [19], recent data suggest
that FA transporters may also be regulated by TRs. Using
radiolabeled FA infusion techniques, it was shown that
FA uptake from TG-rich lipoproteins was increased by TH
in a tissue-specific manner [19]. Hyperthyroidism also
increased TG-derived FA uptake in all oxidative tissues
except brown adipose tissue, whereas hypothyroidism
increased TG-derived FA uptake in lipid-storing white
adipose tissue and decreased its uptake in liver [20].
Moreover, hepatic FAT expression was suppressed in ani-
mal models of postnatal hypothyroidism [21]. Although
these studies indicate that TH may be important in regu-
lating FA uptake in different tissues such as the liver, the
precise mechanism by which TH alters FATP activities
needs further investigation.
TH regulation of hepatic lipogenesis
The synthesis of FFA from acetyl-CoA (de novo lipogenesis)
is regulated through various nuclear hormone receptors,
including liver X receptor (LXR), PPAR, and TR. TH
regulates hepatic lipogenesis by stimulating the transcrip-
tion of three key lipogenic transcription factors that are
known to regulate the expression of genes involved in
lipogenesis: sterol regulatory element-binding protein-1c
(SREBP-1c) [22], LXR [23], and carbohydrate-responsive
element-binding protein (CHREBP) [24]. TH can also di-
rectly increase the transcription of lipogenic enzymes such
as acetyl-CoA carboxylase (ACC), malic enzyme (ME), fatty
acid synthase (FAS), and Spot14 (S14) [25]. Liganded TR
associates with co-activator complex on TH response ele-
ments (TREs) in the promoter region of these genes to
enhance transcription. However, contrary to its positive
regulation of most of the lipogenic genes, TH negatively
regulates stearoyl-CoA desaturase-1 (SCD-1) via a TRE-
independent mechanism in mice [26]. Distinct abnormali-
ties in hepatic lipid metabolism in the PV mutant mouse
model, which mimics a TR mutation in patients with
resistance to TH, have also been reported [27]. Interest-
ingly, whereas livers from TRbPV mice had markedly
increased lipid accumulation, liver mass and lipogenic
gene expression were decreased in TRaPV mice. This
Trends in Endocrinology and Metabolism xxx xxxx, Vol. xxx, No. x
result suggests that, at least in these mouse models,
dominant negative TRb and TRa1 may act on different
repertoires of genes with contrasting effects on hepatic
lipid metabolism [28].
TH regulation of hepatic lipolysis and b-oxidation
Although TH can stimulate lipogenesis, prolonged treat-
ment leads to increased FA oxidation [29]. However, the
mechanism for this switch is currently unknown. Most of
the FAs used for oxidation are derived from FFAs from
adipose tissue via TH-mediated lipolysis. FAs are also
released from TG stores during hepatic lipolysis. Lipases
hydrolyze lipids to form FAs and glycerol. TH does not
seem to significantly alter the gene or protein expression of
classic lipases in the liver, with the exception of hepatic
lipase, which is transcriptionally upregulated by TH [30].
The effect of TH on adipose TG lipase in liver is presently
unclear. TH can also increase the gene expression of zinc-
a2-glycoprotein, a protein that contributes to lipolysis in
hepatocytes [31]. Although it is not known whether hepatic
lipases and zinc-a2-glycoprotein are direct targets of TR,
these findings shed light on a relatively less-studied aspect
of hepatic lipid hydrolysis, which might have a crucial role
in both normal and diseased conditions [32].
Recent studies have shown that autophagy is a key
process in hepatic lipolysis and lipid droplet degradation
[33]. The resultant FFAs released after hydrolysis are
catabolized by b-oxidation within nearby mitochondria.
Moreover, TH was shown to increase lipophagy, a specific
autophagic process used to traffic lipids to the lysosome, in
hepatocytes [34]. In particular, TH significantly increased
the number of lipid-laden autophagosomes and lysosomes
in both human hepatic cells and mouse liver. Although the
precise mechanism used by TH to induce hepatic lipophagy
is not well understood, it is TR-dependent [33]. Addition-
ally, blockade of autophagic flux in cell culture [34] and in
vivo significantly reduced TH-induced ketogenesis, which
is the final step in b-oxidation. Collectively, these findings
suggest that lipophagy is a major mechanism for supplying
FFAs for b-oxidation by TH [34]. Moreover, loss of lipo-
phagy in TRbPV mice correlated with a diminished b-
oxidation capacity and hepatosteatosis [27,34]. Thus, a
decrease in lipophagy due to decreased intracellular TH
levels or TH action may contribute to hepatosteatosis.
Oxidation of FAs to acetyl-CoA occurs within mitochon-
dria, peroxisomes, and the endoplasmic reticulum. FAs are
activated by acyl-CoA-synthetase to acyl-CoA in the cyto-
sol. This process is essential for enabling FAs to cross
membranes and enter organelles. Short (aliphatic tails
of fewer than six carbons in length) and medium-chain
FAs (aliphatic tails of 612 carbons in length) pass the
mitochondrial membrane without activation, whereas ac-
tivated long-chain FAs are shuttled across the membrane
by carnitine palmitoyltransferase-1 (CPT-1) [35]. The gene
expression of CPT-1 and pyruvate dehydrogenase lipoa-
mide kinase isozyme 4 (PDK4), which leads to decreased
glycolysis by phosphorylating pyruvate dehydrogenase,
are positively regulated by TH. Recently, TR was shown
to assemble with the histone deacetylase SirT1 and perox-
isome proliferator-activated receptor gamma coactivator
1a (PGC-1a) on the TREs of their promoters [36]. SirT1 is
3
TEM-976; No. of Pages 8
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crucial for maintaining normal hepatic lipid and glucose
metabolism [37]. TH-bound TR can also increase the
expression of fibroblast growth factor-21 (FGF21) in a
PPARa-dependent manner [38]; FGF21 is a pivotal regu-
lator of mitochondrial activity and b-oxidation in the liver
[39]. However, more recent findings suggest that FGF21
levels may be regulated independent of TH action in vivo
[40]. Finally, in addition to increasing substrate availabili-
ty through increased lipolysis and CPT-1 expression, TH
also increases the biogenesis of hepatic mitochondria by
stimulating PGC-1a expression [41]. Collectively, these
findings suggest that TH strongly induces coordinated
lipid catabolism by stimulating lipophagy-mediated lipol-
ysis and mitochondrial b-oxidation of FA.
TH and regulation of cholesterol homeostasis
Normal serum levels of TH are essential for maintaining a
sufficient pool of cholesterol to meet the bodys require-
ments as well as for regulating the crucial steps of choles-
terol synthesis, uptake, and metabolism [1]. TH regulates
serum cholesterol levels by stimulating its hepatic synthe-
sis, serum uptake, and intrahepatic conversion to bile
acids. TH modestly induces 3-hydroxy-3-methyl-glutaryl
coenzyme A (HMG CoA) reductase and farnesyl pyrophos-
phate gene expression to promote cholesterol synthesis
[42]. However, TH strongly induces the gene and protein
expressions of LDL-R and ApoA1, which increase choles-
terol uptake into the liver [43]. By contrast, patients with
hypothyroidism typically have hypercholesterolemia and
LDL accumulation in the liver, which can be normalized
after TH replacement [9]. Apart from direct stimulation by
TH, the LDL-R gene is subject to regulation by SREBP-2,
which, in turn, is directly regulated by TH [44]. Addition-
ally, the transcription of LDL-R-related protein 1 (LRP-1),
a lipoprotein involved in the removal of chylomicron rem-
nants and very LDL (VLDL), is increased by TH [45].
Recently, other LDL-R-independent mechanisms, such
as increased expression of cholesterol 7a-hydroxylase
(Cyp7A1), the rate-limiting enzyme in the synthesis of bile
acid from cholesterol, or decreased ApoB protein levels,
have been proposed to explain the TH-mediated reduction
of LDL [46,47]. Furthermore, TH-induced secretion of
cholesterol into bile acids is dependent on TH stimulation
of ATP-binding cassette transporter G5/G8 (ABCG5/G8)
complex gene transcription [48]. Finally, in addition to the
transcriptional regulation of genes involved in cholesterol
synthesis and bile secretion, TH may also utilize miRNAs
to regulate these processes. Recently, miRNA-181d was
shown to decrease the expression of caudal type homeobox
2 (cdx2), a regulator of sterol O-acyltransferase 2 (Soat2), a
gene that is crucial for the hepatic secretion of cholesterol
esters; this may represent a novel mechanism for TH to
lower serum cholesterol [49].
Crosstalk of TR-mediated hepatic lipid metabolism with
other nuclear receptor signaling pathways
TR often forms heterodimers with retinoid X receptors
(RXRs) to regulate target gene expression. However, be-
cause RXRs also heterodimerize with several other nuclear
receptors, such as PPAR and LXR, TR heterodimerization
with RXR can influence gene regulation by other nuclear
4
Trends in Endocrinology and Metabolism xxx xxxx, Vol. xxx, No. x
receptors through their mutual competition for a limited
pool of nuclear RXRs [25]. Hashimoto and Mori [50] dem-
onstrated that the D337T TRb mutation, which diminishes
TRRXR heterodimerization, promoted RXR interaction
with LXR and induced the hypocholesterolemic effects of
LXR. Similarly, the dominant-negative TRa P398H muta-
tion, which still enables the mutated TR to heterodimerize
with RXR, interfered with PPARa signaling and activation
of its target genes to impair b-oxidation [51]. Interestingly,
LXRRXR dimers negatively regulated TH signaling by
downregulating the expression of hepatic deiodinase 2 [52].
Apart from competition among nuclear receptors to form
heterodimers with RXR, there can also be competition for
binding to common DNA response elements. In this regard,
transcription of the ATP-binding cassette transporter A1
(A1), which is involved in cholesterol efflux from cells, is
reciprocally regulated by the competitive binding of TR and
LXR to a common direct repeat 4 (DR4) element located on
its promoter [50]. Besides other nuclear receptors, direct
interaction with nuclear co-repressors, such as silencing
mediator for retinoid and thyroid hormone receptors
(SMRT) [53] and nuclear receptor co-repressor (NCoR)
[34,54,55], can also regulate hepatic lipid and cholesterol
metabolism and potentially modify TH signaling. More-
over, distinct isoform-specific effects of TR were also at-
tributed to have selective affinity to NCoR [28]. Thus,
competition among nuclear receptors for RXR, common
DNA sites, and co-repressors and/or co-activators, enables
intricate crosstalk between nuclear receptor signaling
pathways.
Regulation of hepatic lipid metabolism via non-classical
TH signaling
Although most actions of TH are mediated by transcrip-
tional regulation through nuclear TRs, there is evidence for
a non-classical TH signaling pathway that does not require
nuclear TRs [56]. The lipid-lowering effect of TH on FaO
rat hepatoma cells, which are devoid of TRs, engages a non-
receptor-mediated mechanism involving both short-term
stimulation of mitochondrial O2 consumption and long-
term transcriptional effects on PPARs [57]. Additionally,
in contrast to its suppressive effect on mouse SREBP-1c,
TH appears to upregulate the human homolog via a non-
genomic ERK-mediated pathway in HepG2 cells [58]. TH
also increases b-oxidation in HeLa cells through a mecha-
nism that involves an increase in cytosolic calcium and
activation of 50 AMP-activated protein kinase (AMPK) [59].
A deeper mechanistic understanding of non-genomic TH
signaling may help explain some of the acute effects of TH
on hepatic lipid and mitochondrial metabolism, which have
remained elusive so far.
TH regulation of hepatic carbohydrate metabolism
Although the role of TH in carbohydrate metabolism has
been studied for nearly a century, the molecular and
intracellular mechanisms of its regulation have only re-
cently begun to be understood. Clinically, hyperthyroidism
is associated with increased glucose production, absorp-
tion, and utilization, whereas hypothyroidism is charac-
terized by decreased glucose utilization by peripheral
tissues [1]. TH influences glucose metabolism peripherally
TEM-976; No. of Pages 8
Review
through its actions on many organs, particularly the pan-
creas, muscle, adipose tissue, and the liver [60]. TH can
also act centrally to modulate hepatic glucose production
and insulin sensitivity via a sympathetic pathway connect-
ing the paraventricular hypothalamus to the liver, without
any changes in circulating glucoregulatory hormone levels
[61,62].
Hyperthyroidism is known to stimulate hepatic gluco-
neogenesis by increasing alanine transport and its conver-
sion to glucose. TH also directly increases the expression of
both the rate-limiting enzyme in gluconeogenesis, phos-
phoenolpyruvate carboxykinase (PCK1) [63], and glucose-
6-phosphatase (G6PC) [64]. The TH analog GC-1 can acti-
vate transcription of these gluconeogenic genes [25]. Re-
cently, several groups studied the effect of TH on hepatic
glucose production in more detail. It was shown that SirT1
contributes to TH regulation of CPT-1, the acyl-CoA carrier
protein that is important for b-oxidation of FAs [36,64].
SirT1 interacts with liganded TRb1 in vitro to promote its
deacetylation and activation while enhancing ubiquitin-
dependent TRb1 turnover. which is a common response of
nuclear receptors (NRs) to ligand binding [36,64]. Similar-
ly, it was recently reported that FoxO1 is crucial for the
TH-mediated transcription of PCK1 and G6PC [65].
In vivo, FoxO1 siRNA knockdown markedly decreased
the TH-mediated transcription of gluconeogenic genes in
mice [65]. TH also was unable to induce FoxO1 deacetyla-
tion or hepatic PCK1 gene expression in TRb-null (TRb/)
mice [65], suggesting that SirT1 deacetylation and activa-
tion of FoxO1 were TR-dependent. Collectively, these
results raise the possibility that drugs targeting the SirT1
pathway in the liver may also modulate TH regulation of
hepatic target genes involved in lipid and carbohydrate
metabolism.
TH and hepatic insulin resistance
Glucose homeostasis in humans is regulated by insulin
secretion from pancreatic b-cells and glucose metabolism
by insulin-sensitive tissues such as the liver and muscle
[66]. Insulin facilitates glucose utilization in peripheral
tissues and suppresses hepatic glucose production (HGP).
Insulin resistance is often associated with obesity and
predisposes affected individuals to glucose intolerance
and T2DM [67]. Clinically, hyperthyroidism is associated
with impaired glucose tolerance, hepatic insulin resis-
tance, and increased HGP [14,25].
One major connection between glucose metabolism and
TR signaling is the stimulation of ChREBP by TH, a basic
helixloophelix leucine zipper transcription factor that
stimulates the expression of enzymes promoting lipogene-
sis in response to glucose and insulin [68]. Thus, TH can
potentiate inappropriate HGP during insulin resistance as
well as stimulate lipogenesis during hyperinsulinemia.
The overall effects of TH on glucose tolerance and insulin
sensitivity are complex and mixed [14,37,69,70], and some
of its actions on other tissues may counteract, in part, the
insulin resistance and glucose intolerance in the liver. For
example, TH reduces body fat and increases mitochondrial
oxidative metabolism in skeletal muscle, which can in-
crease insulin sensitivity and glucose utilization while it
promotes HGP [25].
Trends in Endocrinology and Metabolism xxx xxxx, Vol. xxx, No. x
Isoform-and liver-specific TH analogs
As mentioned earlier, the tissue-specific distribution of TR
isoforms, TRa and TRb, provides a therapeutic opportuni-
ty for selective TH action in specific tissues such as the liver
[71]. In particular, liver-selective or TRb-specific agonists
can uncouple the beneficial effect of TH on hepatic and
plasma lipids from its deleterious effects on heart and
bone. In this regard, selective thyroid receptor modulators
could potentially be used to treat major metabolic disor-
ders such as obesity, NAFLD, hypercholesterolemia, and
T2DM [7274]. For example, treatment of leptin-deficient
ob/ob mice with a TRb-selective agonist reduced plasma
glucose and improved insulin resistance [25,73,74]. A liver-
selective pro-drug that is metabolized into a TH mimetic
within the liver was also effective in lowering serum
cholesterol and TG levels [75], suggesting that activating
TR specifically in the liver may be a therapeutic approach
towards improving lipid profiles.
TH analogs, hypercholesterolemia, and RCT
TH can decrease serum cholesterol levels in animals and
humans, particularly in combination with statin therapy
[76,77]. The primary mechanism for this beneficial effect is
the enhancement of reverse cholesterol transport (RCT).
Studies in rodents showed that TH and the thyromimetic
compound CGS-23425 increased the plasma levels of
ApoA1 [78], suggesting that TH may promote the synthesis
of high-density lipoprotein (HDL) and influence the initial
step of RCT. Additionally, TH and thyromimetics in-
creased RCT by increasing the expression and activities
of several key proteins involved in cholesterol metabolism,
including the following: scavenger receptor class B member
1 (SRB1), which is responsible for the uptake of cholesterol-
enriched HDL; CYP7A1, which converts cholesterol into
bile acids in the liver; and ABCG5/G8, which promotes
biliary cholesterol excretion [75,7982]. One of the first
chemically synthesized TH analogs was 3,5-diiodothyro-
propionic acid (DITPA). Although beneficial effects were
noted on cholesterol and weight, DITPA resulted in in-
creased serum markers of bone turnover, suggesting that
DITPA has a negative effect on bone [83]. Moreover, cho-
lesterol-independent positive effects of thyromimetics have
been observed in rodent models of atherosclerosis [84].
TH analogs and hepatic carbohydrate metabolism
TRb-specific analogs have favorable effects on lipid metab-
olism; however, it appears that TRa may have some oppo-
site actions to TRb with respect to metabolism. In contrast
to TRbKO and TRbPV knock-in mice, which have in-
creased hepatosteatosis, TRa knockout (Tra-null) mice
were protected from hepatosteatosis and high fat diet-
induced hepatic insulin resistance [85]. Thra-0/0 mice were
also leaner, less sensitive to high fat diet-induced obesity,
and had significantly decreased liver TG and cytosolic
diacylglycerol levels. Along with these changes, insulin-
stimulated p-Akt/Akt ratios were also increased in these
mice compared with wild-type mice. Interestingly, a simi-
lar phenotype was observed in TRaPV knock-in mice when
compared with TRbPV knock-in mice [86]. Collectively,
these findings suggest that development of a TRa antago-
nist may have therapeutic potential. However, it should be
5
TEM-976; No. of Pages 8
Review
noted that knock-in mice expressing another mutant TRa
with a decreased binding affinity for TH exhibited de-
creased metabolic rates and increased visceral fat [87].
These finding raise the interesting possibility that specific
TRa mutations may have variable effects on the metabolic
phenotype. Notably, patients with TRa mutations have
recently been identified, and these patients show increased
body mass index values and decreased metabolic rates
[88,89].
In addition to TR isoform-specific or liver-specific ana-
logs, TH metabolites may also have beneficial effects on
hepatic metabolism. Recently, the diiodothyronine (T2)
mimetic TRC150094 was developed for the treatment of
heart failure, dyslipidemia, and diabetes. As TRC150094
has very low affinity for both TRa and TRb isoforms, it is
thought to enhance the mitochondrial oxidative capacity in
liver via the increased activity of complex V [74]. The
development and use of TR-independent analogs opens
new avenues for the treatment of metabolic disorders
through their non-genomic actions.
TH and analogs in treating NAFLD
NAFLD is a major global health problem that is associated
with obesity and insulin resistance [90]. Its pathogenesis
remains poorly understood, and, currently, there are no
approved drug therapies [91]. As mentioned earlier, there
exists a strong association between hypothyroidism and
NAFLD [7,92]. This association seems plausible because
clinical thyroid dysfunction can lead to hyperlipidemia,
obesity, and insulin resistance, all of which are major
components of metabolic syndrome [93] and are implicated
in the pathogenesis of NAFLD. In human NAFLD micro-
array studies, hepatic lipid accumulation caused the down-
regulation of a set of TH-responsive genes, including some
that were involved in energy metabolism [8]. In rodent
models of NAFLD, TH analogs were effective in reducing
hepatosteatosis [71,94,95]. In this regard, TH induction of
lipolysis via lipophagy and its concomitant increase in b-
oxidation may help reduce TG loads in the liver [34].
However, because increased peripheral lipolysis occurring
in adipose tissue and adverse cardiac side effects are
matters of concern, receptor isoform-specific and hepatic-
targeted TH analogs have been developed [96]. Interest-
ingly, TH analogs that are unable to bind TRs were also
effective in reducing hepatosteatosis and in increasing
hepatic lipid metabolism [9799]. Thus, utilization of TH
analogs, inhibition of unliganded TR action [85], or modu-
lation of co-repressor activity [53,100] may be viable ther-
apeutic strategies for treating NAFLD.
Concluding remarks and future perspectives
The mammalian liver has been a classic organ for studying
TH action. TH regulates both hepatic lipid and carbohy-
drate metabolism in a multi-layered and complex manner
(Figure 2). Our current understanding of the actions of TH
on the liver has progressed from the early characterization
of its physiological effects to the elucidation of the regula-
tion of specific target genes and the complex molecular
interactions involved in metabolic programming. In
particular, we have begun to understand the network
of hormonal stimuli, intracellular energy status, cell
6
Trends in Endocrinology and Metabolism xxx xxxx, Vol. xxx, No. x
Box 1. Outstanding questions
 What is the mechanism(s) by which TH activates SIRT1 to regulate
lipid and glucose homeostasis?
 What is the role of miRNAs in the TH regulation of hepatic lipid
and carbohydrate metabolism?
 How does TH signaling crosstalk with hepatic insulin signaling
and how does it contribute to insulin resistance?
 Is there intrahepatic TH resistance that triggers fatty liver
development?
signaling pathways, and transcription factor crosstalk that
are affected by TH regulation of carbohydrate and lipid
metabolism in normal and pathological conditions. Given
the global rise of metabolic disease, a better understanding
of the physiological, metabolic, and molecular relation-
ships between TH action and metabolism may lead to
improved therapies for these diseases. Indeed, future stud-
ies in these areas (Box 1) may help determine whether
NAFLD, insulin resistance, and dyslipidemia in subclini-
cal hypothyroidism, or hyperglycemia in subclinical hyper-
thyroidism, warrant correction of serum or intrahepatic
TH levels. Intrahepatic TH levels could potentially be
assessed by measuring serum protein and metabolomic
markers. Finally, a better understanding of TH action and
hepatic metabolism may also lead to the development of
new and safe thyromimetics that could be beneficial for the
treatment of metabolic conditions such as hyperlipidemia,
NAFLD, T2DM, and obesity.
Acknowledgments
This manuscript was supported by grant NMRC/CIRG/1340/2012 to
P.M.Y. from the National Medical Research Council, Singapore.
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