BIOC460-DR.

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

CH2----OOC-R1 CH2OH HOOC-R1

|
R2-COO----CH

|
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

acetyl-CoA TCA [7]

cycle
A
[3]
[4] C
-oxidation
[6]
S
FA
acyl-CoA
acyl-CoA
FABP
FABP
[5]
carnitine
CYTOPLASM
transporter

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

CH3-(CH)12-C-S-CoA + Acetyl CoA

O

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