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TISCHLERLECTURE33
LIPOLYSIS:FATOXIDATION&KETONES
OBJECTIVES
1. Lipolysis
a)describethepathway;
b)location
c)principalenzyme
d)role
e)roleofalbuminandFABPintransport/metabolismofFFA
2. DegradationoffattyacylCoA
a)rolesofacylCoAsynthetase,CPT-IandCPT-II,andCAT
b)relationshipof-oxidationproductstoenergyproduction.
c)degradationofodd-vseven-chainFA
d)vitaminsformetabolizingpropionylCoAtosuccinylCoA
3. Ketonebodymetabolism
a)whereketogenesisoccurs
b)whenketogenesisoccurs
c)roleofkeotgenesis
d)whynormalindividualsdonotusuallydevelopketacidosis
evenwhenproducingketonebodies.
FATFACTS
fat(lipid)makesup37%ofthecaloriesintheAmerican
diet
energyrichandprovides9kcal/gm
dietarylipids90%triacylglycerols(TAGs)alsoinclude
cholesterolesters,phospholipids,essential unsaturated
fattyacids;fat-solublevitamins
mostdietaryfattransportedtoadiposeforstorage
dietaryTAGshydrolyzedintheintestinebypancreatic
lipases;thenreassembledintheintestinalcells
dietaryfatstransportedtotissuesasTAGorcholesterol
viachylomicrons
atperipheraltissues(e.g.,adiposeormuscle),FAremoved
fromtheTAGbyalipoproteinlipaseinthecapillary
walls;releasedfattyacidsdiffuseintothecell
saturatedfattyacid:
CH3-(CH2)n-COOH
unsaturatedfattyacid:
CH3-CH=CH-(CH2)n-COOH
polyunsaturatedfattyacid:
CH3-CH=CH-CH2-CH=CH-(CH2)n-COOH
|
Lipolysis
CHOHHOOC-R
||
CH2----OOC-R3CH2OHHOOC-R3
Triacylglycerol
Glycerol
Fattyacids
Figure1.Generalstructuresoffattyacidsand
triacylglycerol.Lipolysisofstoredtriacylglycerolby
lipasesproducesfattyacidsplusglycerol.
LIPOLYSIS
fattyacidshydrolyticallycleavedfromtriacylglycerol
largelyinadiposetoreleasefattyacidsasafuel
mayalsooccurinmuscleorliver-smalleramountsof
fattyacidsarestored
hormone-sensitive(cyclicAMP-regulated)lipase
initiateslipolysiscleavesfirstfattyacid
thislipaseandothersremoveremainingfattyacids
fattyacids/glycerolreleasedfromadiposetothe
blood
hydrophobicfattyacidsbindtoalbumin,intheblood,
fortransport
CAPILLARY
Lipoproteins
(Chylomicrons
or VLDL)
FA
FA
albumin
FA
[1]
fro
m
fat
cell
L
P
L
[2]
FA
FABP
FA
MITOCHONDRION
cellmembrane
FA=fattyacid
LPL=lipoproteinlipase
FABP=fattyacidbindingprotein
ACS=acylCoAsynthetase
Figure2.Overviewoffattyaciddegradation
ATP + CoA
AMP + PPi
palmitate
palmitoyl-CoA
Cytoplasm
ACS
CPT-I
[2]
[1]
CoA
palmitoyl-CoA
Intermembrane
Space
OUTER
MITOCHONDRIAL
MEMBRANE
carnitine
palmitoyl-carnitine
Figure3(top).ActivationofpalmitatetopalmitoylCoA
(step4,Fig.2)andconversiontopalmitoylcarnitine
CPT-I
palmitoyl-CoA
Intermembrane
Space
CoA
palmitoyl-carnitine
carnitine
CAT
Matrix
[3]
INNER
MITOCHONDRIAL
MEMBRANE
CPT-II
carnitine
palmitoyl-CoA
[4]
palmitoyl-carnitine
CoA
Figure3(bottom).Mitochondrialuptakeviaofpalmitoylcarnitineviathecarnitine-acylcarnitinetranslocase(CAT)
(step5inFig.2).
ATP + CoAAMP + PP
i
palmitate
Cytoplasm
palmitoyl-CoA
ACS
[1]
OUTER
MITOCHONDRIAL
MEMBRANE
CPT-I
[2]
CoA
palmitoyl-CoA
carnitine
Intermembrane
Space
palmitoyl-carnitine
CAT
[3]
INNER
MITOCHONDRIAL
MEMBRANE
CPT-II
Matrix
carnitine
palmitoyl-CoA
[4]
palmitoyl-carnitine
CoA
Palmitoylcarnitine
Carnitine
respiratory chain
translocase
inner mitochondrial
membrane
Palmitoylcarniti
matrix side ne
2 ATP
Palmitoyl-CoA
FAD
oxidation
FADH2
H2O
hydration
recycle
6 times
oxidation
NAD+
NADH
cleavage
Figure4.
Processingand
-oxidationof
palmitoylCoA
CoA
3 ATP
Citric
acid
cycle
2 CO2
OXIDATIONOFODD-CHAINFATTYACIDS
Finalstepof-oxidationproduces:
propionylCoA+acetylCoA
propionylCoAcarboxylase:(biotin-dependent)
propionylCoA+ATP+CO2
methylmalonylCoA+AMP+PPi
methylmalonylCoAmutase:
(adenosylcobalamin-dependent)
methylmalonylCoAsuccinylCoA
Figure5.Reactionsinthemetabolismofpropionyl
CoAderivedfromodd-chainfattyacids
Fatty acid
-oxidation
MITOCHONDRION
oxidation to
2 Acetyl CoA
CO2
(excess
Thiolase
acetyl CoA)
CoA
acetyl CoA
Citric
acid
cycle
Acetoacetyl CoA
Figure6.Ketone
HMG-CoAsynthase
bodyformation
CoA
(ketogenesis)inliver
Hydroxymethylglutaryl CoA
mitochondriafrom
excessacetylCoA
HMG-CoA-lyase
derivedfromthe- acetyl CoA
oxidationoffatty
Acetoacetate
acids
NADH
(non-enzymatic)
-Hydroxybutyrate
dehydrogenase
Acetone
NAD+
-Hydroxybutyrate
KETONEBODYOXIDATION
highratesoflipolysis(e.g.,longtermstarvationorin
uncontrolleddiabetes)producesufficientketonesinthe
bloodtobeeffectiveasafuel
ketonesarethepreferredfuel ifglucose,ketones,fattyacids
allavailableintheblood
primarytissues:usingketones,whenavailable,arebrain,
muscle,kidneyandintestine,butNOTtheliver.
-Hydroxybutyrate+NAD+acetoacetate+NADH
-hydroxybutyratedehydrogenaseinmitochondria;
reverseofketogenesis
KETOACIDOSIS
Excessivebuild-upofketonebodiesresultsinketosiseventually
leadingtoafallinbloodpHduetotheacidicketonebodies.
Indiabeticpatientstheeventsthatcanleadtoketosisare:
Relativeorabsolute(mostcommoncause)deficiencyofinsulin
Mobilizationoffreefattyacids(fromadiposelipolysis)
Increaseddeliveryoffreefattyacidstotheliver
Increaseduptakeandoxidationoffreefattyacidsbytheliver
Acceleratedproductionofketonebodiesbytheliver
Adipose
Tissue
Free fatty
acids
Liver
KetoneBodies
Insulin
Pancreas
Figure7.Mechanismforpreventionofketosisdueto
excessketonebodyproductionthatcanleadtoketoacidosis