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Lipid MetabolismRemember fats??Triacylglycerols - major form of energy storage in animals
Your energy reserves:~0.5% carbs (glycogen + glucose)~15% protein (muscle, last resort)~85% fat
Why use fat for energy?1 gram fat = at least 6-fold more energy than 1 gram carb
Sources of fat:1. Diet2. Stored fat (adipose tissue)3. Fat synthesized in one organ for export to another
(excess carb converted to fat)
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Lipid MetabolismHow can insoluble dietary fats be metabolized?
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Lipid MetabolismHormones trigger mobilization of stored triacylglycerols
Also heart, renal cortex
Epinephrine, glucagon
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Lipid MetabolismHow are fatty acids burned for energy?
1. Transported to mitochondria2. Oxidized to produce acetyl CoA, NADH, FADH2
3. Acetyl CoA goes to citric acid cycleNADH, FADH2 donate e- to oxidative phos
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Lipid MetabolismOxidation of fatty acids - fatty acid breakdownTransport of fatty acids into mitochondria“Prime” fatty acid
Dri
ves
reac
tion
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Lipid MetabolismOxidation of fatty acids - fatty acid breakdownTransport into mitochondria using carnitine intermediate
Carnitine recycledCytosolic and mitochondrial CoA pools stay balanced
(CoAmatrix used for ox degrad of pyruvate, fatty acids, amino acids)(CoAcytosol used for fatty acid biosynthesis)
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Lipid MetabolismOxidation of fatty acids - fatty acid breakdown-oxidation of fatty acids (even # carbons)
oxidized
reducedDonates 2e- to Q (ox phos)
oxidation
hydration
oxidation
thiolysis
Citric acid cycle
Fatty acid shortened by 2 carbon atoms, cycle through -oxidation again
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Lipid MetabolismOxidation of fatty acids - fatty acid breakdown-oxidation of fatty acids
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Lipid MetabolismOxidation of fatty acids - fatty acid breakdown-oxidation of fatty acids (odd # carbons)-oxidation gives a 3 carbon remnant
Need ATP to put CO2 on biotin
(Citric acid cycle intermediate)
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Lipid MetabolismOxidation of fatty acids - fatty acid breakdown-oxidation of fatty acids (unsat’d, double bonds)
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Lipid Metabolism
Oxidation of fatty acids - regulation
Need to regulate so oxidation only occurs when the need for energy requires it
1. Rate-limiting rxn. - fatty acids entering mito. (acyltransferases)
2. Malonyl CoA (important molecule!!)1st intermediate in biosynthesis of fatty acidsincreases when lots carbohydratespresence of it inhibits carnitine acyltransferase I ensures that oxid of FA inhibited when liver has a lot of glc
3. [NADH]/[NAD+]
4. [acetyl CoA]
High [NADH]/[NAD+]
High [acetyl CoA]
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Lipid Metabolism
Ketone Bodies
In the liver, some acetyl CoA is exported to blood as “ketone bodies” for use in other tissues, rather than burned in liver by the citric acid cycle
During fasting, carbs not available to replenish cycle intermediates - so ketogenesis takes over
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Lipid Metabolism
Ketone BodiesSoluble, transportableReconverted back to acetyl CoA in other tissuesFuel for heart muscleMajor fuel for brain (starvation)
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Lipid Metabolism
Ketone Bodies
exhaled
Transported to tissues other than liver, oxid in TCA cycle
Brain usually uses glc as fuel but in times of starvation, adapts to using acetoacetate or D--Hydroxybutyrate
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Lipid Metabolism
Ketone BodiesMajor fuel for heart muscleMajor fuel for brain (starvation)
TCA
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Lipid Metabolism
Ketone Bodies overproduced in starvation and diabetes
Starvation gluconeogenesis (need to be making glc) depletes TCA intermediates, diverting acetyl CoA to ketone body production
DiabetesNot enough insulin, tissues cannot take up glc efficiently from blood to use as fuel or store as fatMalonyl CoA (fatty acid biosynthesis) not formed, so carnitine acyltransferase I not inhibitedFatty acids enter mitochondria to be degraded to acetyl CoA (which cannot go to TCA because cycle intermediates have been used in gluconeogenesis) Accumulating acetyl CoA accelerates ketone body formationIncreased acetone toxic, acetone volatile, characteristic odor to breathIncreased acetoacetate or D--Hydroxybutyrate lowers blood pH causing acidosis (coma, death)Lots of ketones in urine causes ketosis (ketoacidosis)
Low carb/high protein dietsEnd up using stored fats as energy source, levels of ketone bodies in blood and urine increase (ketoacidosis)
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Lipid Metabolism
Lipid BiosynthesisMost calories in diet = carbs, stored calories = fatsHow do we convert sugar to fat?
Lots of lipid biosynthesis in liver, lipids exported through blood to other tissues as lipoproteins
Class Major lipid carried OriginChylomicrons dietary triacylglycerols intestineVLDL endogenous triacylglycerols liverLDL endogenous cholesterol liverHDL cholesterol liver, intestineSerum albumin fatty acids fat cells
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Lipid Metabolism
Lipid BiosynthesisPolymerize acetyl CoA into fatty acids, join them to glycerol to make triacylglycerolReverse of -oxidation, but enzymes and control are different
-oxidation - mitochondria, FA biosynthesis - cytosol
First committed step - acetyl CoA carboxylase
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Lipid Metabolism
Lipid BiosynthesisFatty acid synthaseGrowing FA chain-thioester
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Lipid Metabolism
Lipid BiosynthesisRepeating the process
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Lipid MetabolismLipid BiosynthesisFatty acid synthaseSeven enzyme activities in one
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Lipid MetabolismLipid BiosynthesisNADP+ carries reducing power for FA biosynthesisSources of NADP+ = malic enzyme, pentose phosphate pathway
Separate pools of reducing power NADPH for biosynthesisNADH for energy production
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Lipid MetabolismRegulationCommitted steps-oxidation - rate limiting step = acyltransferases
No futile cyclesMalonyl CoA - high [] signals FA synthesis and inhibits carnitine acyltransferase (blocks entry of FA into mito & blocks -oxid.)
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Lipid MetabolismSynthesis of cholesterol
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Lipid MetabolismSynthesis of cholesterol - regulation
1. HMG CoA reductase is nonequilibrium rxn and committed step
2. Cholesterol inhibits HMG CoA reductase (feedback inhibition)
3. Metabolites in cholesterol biosyn. pathway inhibit HMG CoA reductase (feedback inhibition)
4. Cholesterol also activates a protease that degrades HMG CoA reductase
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Lipid MetabolismSynthesis of cholesterol
Cholesterol synthesized in liver
Delivered to tissues through blood as LDL/HDL particlesLDL receptor on cell surface binds protein component of LDL and allows cell to internalize LDL
Heart disease & cholesterolCholesterol in blood forms deposits inside arteries (narrowed)Heart disease correlates with high serum cholesterol
<175 mg/100 mL is “good”
Familial hypercholesterolemiaHomozygous: 600 mg/100 mL - die in childhoodHeterozygous: 300 mg/100 mL - variable results
Primary defect: LDL receptors absent, [cholesterol] in cell low, so HMG CoA reductase always ON full blast!!
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Lipid MetabolismHeart disease & cholesterolRational prevention of heart disease
Lovstatin, inhibitor of HMG CoA reductaseMimics natural substrate - competitive inhibitorBlocks cholesterol biosynthesis & lowers serum cholesterol