Lipid Metabolism

Overview of Lipid Metabolism

Importance: Fat stores 9 Cal/g (no water) Carbohydrate stores 4 Cal/g (water associated) Protein stores 4 Cal/g (water associated) Alcohol (undergraduates 4th major food group) stores 7 Cal/g (reason 63 not to drink) Few free fatty acids: for human serum total lipid averages 570 mg/dL (450-1,000) FFA 12 mg/dL- (this bound to albumin) dietary TAGs, PLs

Lipid Metabolism Occurs in Three Tissues

Intestine (dietary fat absorption) Liver (fat synthesis and export between meals) Extrahepatic Tissues

Lipoproteins are Responsible for Transport and Mobilization of Fat

Fig. 17-2 Lehninger POB 4th Ed.

Chylomicrons are formed from fat absorption VLDL secreted by liver have analogous (but not identical) structure i.e. phospholipid shell with apolipoproteins (and varying amounts of cholesterol) and TAG core Function differs chylomicrons from meals, VLDL between meals

Chylomicrons
Made by intestine
90-1000 nm diameter Density <0.95 1-2% protein 88% TAG 8% PL 3% CE 1% C trace FFA

vs. VLDL
Made by liver
30-90 nm diameter Density 0.95-1.006 7-10% protein 56% TAG 20% PL 15% CE 8% C 1% FFA

CR and HDL
Fat is low density, protein is high As these pass extrahepatic tissue, fat is extracted as needed Chylomicron remnants (CR, of chylomicrons) and HDL (remnants of VLDL) Some people get less of their VLDL to HDL (the ratio is what you would want looked at)

Some of the Apoproteins

Apoprotein Lipoprotein Apo B-48 Size, kDa Comments Synthesized in intestine Synth in liver, ligand of LDL-R Activator of LCAT Ligand of HDL-R ?Inhibitor of LCAT ?lipid transfer protein Activator of lipoprotein lipase Chylomicrons 260 and CRs Apo B-100 VLDL, LDL, IDL, 550 HDL Apo A-I HDL, Chylo 28 Apo A-II Apo D Apo C-II HDL, Chylo Subfraction of HDL VLDL, HDL, chylo 17 19.3 8.9

Hormone Sensitive Lipase

O CH2O C R O H C O C R' O CH2O C R" 3 H2 O CH2OH H C OH CH2OH Insulin Glucagon R' R" hormone sensitive lipase O R C O O C O O C O

Phospholipase Specificity
Phospholipase A1 O Phospholipase A2 1CH2O C O H C O C unsaturated fatty acid O
3 2

saturated fatty acid

CH2O P O O

Phospholipase C

Phospholipase D

Phospholipases A1 and A2

O CH2O C R O H C O C R' O O Phospholipase A1, A2 2 H 2O

O R C O O R' CH2OH H C OH O O C O CH3 CH3

CH3 CH3

CH2O P O CH2CH2 N CH3

CH2O P O CH2CH2 N CH3

-Oxidation
Importance Location Activation: outer mitochondrial membrane -Oxidation: mitochondrial matrix Reactions Energetics Regulation

Activation of Fatty Acids

CH3 CH2 nCO2 Acyl CoA Synthetase CoASH ATP H2O AMP + PPi inorganic pyrophosphatase H2O Pi O CH3 CH2 nC S CoA

PPi

Pi

Synthetase vs. synthase reminder Pyrophosphatase provides directionality

Transport of Activated Fatty Acids into the Mitochondria

Acylcarnitine Acylcarnitine

. CO2 CH2 HO C H CH2 CH3 N CH3 CH3 .

CoASH CoASH CAT-I Fatty-acyl CoA carnitine-acylcarnitine antiporter CAT-II Fatty-acyl CoA

Carnitine

Carnitine

Carnitine palmitoyl transferase I Carnitine-acylcarnitine translocase Carnitine palmitoyl transferase II CAT-I inhibited by malonyl CoA

Reactions of -Oxidation
Know name and structure of all metabolites Know name of all enzymes and coenzyme/cofactor requirements

Vitamin Thiamin (B1) Riboflavin (B2) Pyridoxine (B6) B12 Folic acid Biotin Niacin Lipoic acid Pantothenic acid

Coenzyme Form Thiamine pyrophosphate (TPP) FAD Pyridoxal phosphate (PLP) Coenzyme B12 Tetrahydrofolate (THF) Biocytin Nicotinamide Lipoate Coenzyme A, aka CoASH

Function Aldehyde group transfer Hydride group tansfer Amino group transfer Alkyl group transfers One-carbon transfers CO2 fixation Hydride group transfer Acyl group transfer Acyl group transfer

-Oxidation of Monounsaturated Fatty Acids

Fig. 17-9 Lehninger POB 4th Ed.

Requires 1 additional enzyme lose 2 ATP per double bond

-Oxidation of Polyunsaturated Fatty Acids

Fig. 17-10 Lehninger POB 4th Ed.

Requires 1 additional enzyme (in addition to the additional enoyl CoA isomerase required for monounsaturated) lose 3 ATP per additional double bond

-Oxidation of Odd-Chain Length Fatty Acids

O propionyl CoA carboxylase biotin HCO3 ATP ADP +Pi O CH3CHC ~ SCoA CO2 D-methylmalonyl CoA

Same as saturated but end with 3C converted to succinyl CoA

CH3CH2C ~SCoA propionyl CoA

O CH3CHC ~SCoA CO2 D-methylmalonyl CoA methylmalonyl CoA epimerase CH3CHCO2 C ~ SCoA O L-methylmalonyl CoA

CO2 CH3CHCO2 C ~ SCoA O L-methylmalonyl CoA methylmalonyl CoA mutase B12 CH2 CH2 C ~ SCoA O succinyl CoA

Ketone Bodies
3: Acetone, acetoacetate and hydroxybutyrate normally low amounts amount increases in diabetes and starvation

Ketone Body Synthesis I

O CH3 C SCoA O CH3 O CH3 C O CH2 C SCoA CoASH H2O SCoA C O thiolase CoASH SCoA HMG-CoA Synthase CH3 O CH3 OH CH3 C CH2CO2 O HMG-CoA CH3 C SCoA O CH2 C SCoA HMG-CoA Lyase CH3 C OH C CH2CO2 HMG-CoA O CH2 C SCoA CH3 C O CH2 C SCoA Acetoacetyl CoA

Acetoacetyl CoA

O C CH2CO2

Ketone Body Synthesis I

O CH3 Spontaneous O CH3 C CH2CO2 -hydroxybutyrate dehydrogenase OH NAD+ CH3 C CH2CO2 H D--hydroxybutyrate CO2 C CH3

Acetoacetate NADH + H+

Fatty Acid Biosynthesis

Location: Cp of many tissues Differences from -ox
NADPH D- instead of L-intermediates

Enzymes
acetyl CoA carboxylase (regulation) fatty acid synthase

Product: palmitic acid

Fatty Acid Elongation

Location: ER Enzymes
3-ketoacyl CoA synthase reductase hydratase reductase

Product: acyl CoA

Trig Formation
Sources of glycerol Enzymes
glycerol kinase G3P acyltransferase phosphatase DAG acyltransferase

Product

PC Formation in Mammals
choline phosphocholine CDP-choline PA PC