lipid metabolism 1. ex biochem c7-lipid metabolism 2 structure of fatty acids carboxylic acid, with...

Lipid Metabolism

1

Ex Biochem c7-lipid metabolism 2

Structure of fatty acids Carboxylic acid, with long alkyl chain

Short chain: 4-6 carbons Medium chain: 8-12 carbons Long chain: 14 or more carbons

Saturated, monounsaturated (MUFA), polyunsaturated (PUFA) Double bonds always in cis formation

Usually use common name or abbreviation Linoleic acid: 18:2 (9,12) or 18:2△9,12

n-3 (or -3) and n-6 (or -6) : the position of the last double bond from the end carbon

Essential FA: linoleic acid, a-linolenic acid Arachidonic acid as precursor for eicosanoids

(prostaglandins, thromboxanes, leukotrienes), paracrine

n-3 (-3), n-6 (-6) fatty acids



Types of lipids Triacylglycerol, triglyceride

Glycerol + 3 fatty acids (saturated or unsaturated) Also diacylglycerol, monoacylglycerol Structure of FAs decide physical and physiological

functions of TG Phospholipids

Derivatives of phosphatidic acid Major components of cell membrane, hydrophilic and

hydrophobic Phosphatidylcholine (lecithin 卵磷酯 ) Phosphatidylinositol important in cellular signaling Phospholipase C produce inositol 1,4,5-triphosphate, act

on endoplasmic reticulum to release Ca, activate other enzymes


Fat stores FA obtained mainly from food fat

Dietary fat digested to glycerol, FAs with small amount of DAG and MAG

Absorbed by intestinal cells, formed TG Chylomicron released into lymphatic system Liver makes and secretes VLDL

Lipoprotein lipase free FAs in lipoproteins LPL synthesized in adjacent fat cells, secreted from the

cell, attached to endothelial lining of nearby capillary FA diffuse into adjacent adipocytes through specific

carrier LPL also present in capillary in skeletal muscle


Formation of TAG Fat synthesis is favored following a meal

Stimulated by insulin In cytosol

FA must be activated by attaching to CoA Acyl CoA synthetase

Glycerol 3-phosphate from glycolysis From dihydroxyacetone phosphate by glycerol phosphate

DHase (in glycerol phosphate shuttle) Acyl transfer to glycerol-3-P

Glycerol phosphate acyltransferase to form phosphatidate Phosphatidate phosphatase, then add another FA


adipocyte


Coenzyme A


Lipolysis

Favored under increasing energy needs Exercise, low-calorie dieting, fasting

Catalyzed by hormone-sensitive lipase In adipocyte, muscle fiber In cytosol


Lipolysis

Ex Biochem c7-lipid metabolism 20Regulation of TAG turnoverin adipocyte

Lipid droplets surrounded by perilipins A protein family, make lipid droplet inaccessible to HSL

Epinephrine, norepinephrine↑lipolysis, insulin↓lipolysis Through cAMP and several kinase Combination of HSL and perilipin phosphorylation ↑lipolysis by

>90 fold, concerted interaction Insulin↑protein kinase B (Akt), ↑PDE, ↓cAMP Balance between prolipolysis beta-adrenergic receptor and

antilipolysis alpha2-receptor determine how easily fat can be mobilized, can be changed by weight reduction or exercise

PKA activate ERK1/2 (a MAP kinase), ↑HSL Growth hormone, cortisol, testosterone ↑lipolysis, in addition to

effect of epinephrine Adenosine, estrogen ↓lipolysis

Ex Biochem c7-lipid metabolism 22Regulation of TAG turnoverin muscle fiber

Theoretically, TAG synthesis and lipolysis can be fully active at the same time in muscle and adipocyte Although usually one is favored the other

Muscle HSL regulated similar to adipocyte No perilipin in skeletal muscle

Other regulatory factors in muscle fiber Elevated Ca can activate several kinases, including PKC Increased AMP activated AMPK Exercise, as a stressor, activate ERK Phosphorylation of HSL by PKA and ERK are 2 most

likely mechanism for ↑lipolysis in muscle


Regulation of lipolysis through HSL


Fate of FA and glycerol TAG-FA cycle

Continuous 50-70 g fat turnover per day Lifetime of TAG in fat cell > 6 months Continuous circle of lipolysis and re-esterification with

fat cell or between tissues In postabsorptive state, fat cells provide FA for

oxidation by other tissues All glycerol generated by lipolysis released to blood

because glycerol kinase is low in fat cells blood [glycerol] as marker for lipolysis rate

~30% FA released during lipolysis undergo re-esterification


Fate of FA and glycerol Glyceroneogenesis

Synthesis glycerol 3-P from lactate, pyruvate, some amino acids

Not from glucose because glucose is used for energy in brain during fasting

Key enzyme PEPCK expression turn on rapidly in postabsorptive state, turn off when glucose available

Cortisol upregulate PEPCK in liver produce glucose, but downregulate PEPCK in adipocyte stimulate FA release

Glycerol released into blood, metabolized by other tissues, mostly liver High glycerol kinase activity Glycerol important source for gluconeogenesis during

fasting/starvation


Fate of FA and glycerol Free fatty acid (FFA)

Or nonesterified fatty acids, NEFA Increased during exercise Most FA in blood bind to albumin Adipose tissue blood flow may limit delivery of FA from adipocyte

to skeletal muscle FFA taken up by liver, re-esterification

VLDL, LPL, FA into adipocyte, incorporated into TAG and stored High blood [FFA] in obesity

In obese individuals, cause insulin resistance Thiazolidinediones (TZDs) ↓blood [FFA], ↓insulin

resistance Agonist for peroxisome proliferator-activated receptor (PPAR- ) Control glycerol kinase, PEPCK in adipocyte ↑glycerol 3-P synthesis, ↑re-esterification of FA


Recycling of TAG in adipocyte


Oxidation of FA Intracellular transport of FA

FA can diffuse through cell membrane In skeletal muscle, plasma membrane fatty-acid binding

protein (FABPpm), fatty acid translocase (FAT/CD36) Endurance training (or high fat diet) increase FABPpm Intracellular store of FAT/CD36 that can be mobilized to

muscle sarcolemma with onset of exercise (similar to GLUT-4)

Cytosolic fatty acid-binding protein (FABPc) FA acyl CoA by acyl CoA synthetase FA + ATP + CoA fatty acyl CoA + AMP + PPi

(pyrophosphate)


Oxidation of FA Transport as acylcarnitine 肉鹼

Need to enter mitochondria for oxidation Carnitine palmitoyl transferase I (CPT I) in mitochondrial outer

membrane (palmitate, C16:0) Carnitine-acylcarnitine translocase to transfer across inner

membrane CPT II in matrix side of outer membrane to form acyl CoA beta

oxidation Beta-oxidation: produce acetyl CoA

Change carbon 3 (beta-carbon) from CH2 to C=O, then introduce a CoA group, cleaving off acetyl CoA

For n-3 PUFA, enoyl CoA isomerase convert double bond from cis to trans, for enoyl CoA hydratase

For n-6 PUFA, reductase convert C=C in wrong postion to C-C For odd-carbon FA, final product propionyl CoA (3 carbons)

converted into succinyl CoA, enter CAC or for gluconeogenesis

Ex Biochem c7-lipid metabolism 33FA transport through mitochondrial membrane


Ketone bodies 酮體 Water-soluble energy-providing lipids

Acetoacetate, D-3-hydroxybyturate, acetone Formation accelerated when CHO content and

insulin is extremely low Starvation/fasting, very low-CHO diet, exercise without

sufficient CHO supplementation, uncontrolled diabetes Adipocyte release large amount of FAs due to imbalance

between TAG formation and lipolysis Low insulin cause lipolysis greatly exceed TAG

formation, large↑blood FFA Liver extract FFA (>30%), form acetyl CoA at rate far

exceed CAC capacity, low oxaloacetate due to low CHO Acetyl CoA acetoacetate


Ketone bodies Used as fuel for mitochondria in extrahepatic tissues

Skeletal muscle, heart, brain When glucose unavailable

Ketosis: prolonged depletion of body CHO, uncontrolled DM

Ketonemia, ketonuria, acetone breath, elevated blood [FFA], acidosis

Benefit for exercise? Ketones can be useful fuel during submaximal exercise, sparing use

of glycogen and blood glucose Ketogenic diet for > 1 week, enhanced ketone bodies use during

exercise ↑activity of enzymes needed to for ketone bodies acetyl CoA in

mitochondria, reduce the need to provide CAC with acetyl CoA from pyruvate


Ketone bodies


Formation of ketone bodies


Formation of acetoacetate


Ketone bodies as fuel for mitochondria


Synthesis of fatty acids Most FA used by humans come from dietary fat

Humans can synthesize FA from acetyl CoA in liver, mammary gland, adipocyte, in minor amount, de novo lipogenesis

Excess CHO converted to acetyl CoA for FA synthesis, smaller amount of acetyl CoA from amino acids, alcohol

Pathways Start with 3-carbon malonyl CoA


Synthesis of fatty acids Continuous supply of acetyl CoA in cytosol

Most acetyl CoA formed in mitochondria Citrate as shuttle to bring acetyl CoA from mitochondria

to cytosol Glucose pyruvate acetyl CoA (in mito) citrate

acetyl CoA (in cytosol) Supply of NADPH

Pentose phosphate pathway Malic enzyme Malate + NADP > pyruvate + CO2 + NADPH + H+

Fatty acid synthase: large enzyme contain 7 distinct enzyme activities Acyl carrier protein


--+


Triacylglyceride synthesis

Ex Biochem c7-lipid metabolism 50FA do not form glucose


Regulation of FA synthesis DNL minor to overall energy balance in average person on

typical mixed diet Acetyl CoA carboxylase key site for regulation

↑by citrate, ↓by fatty acyl CoA, malonyl CoA Inhibited by PKA and AMPK (AMPK activated by↑AMP) Phosphorylation/dephosphorylation depend on insulin/glucagon

Dietary control high-CHO diet↑expression of ACC, FAS high-fat diet↓expression of ACC, FAS insulin↑de novo lipogenesis

Malonyl CoA inhibit CPT1 ↓FA oxidation in mitochondria

People become obese when excess food intake Excess energy in CHO, use more CHO and less fat as energy Excess CHO converted to FA or used as source for glycerol 3-P to

help store even small amount of dietary fat


Fat as fuel for exercise Plasma FFA gradually increase during prolonged

exercise Compared to: blood glucose maintained steady during

exercise lasting up to 60 min Increase in lipolysis during exercise by epinephrine,

decrease re-esterification of fatty acids in adipocytes Lower [FFA] during exercise in fed state

Greater oxidation of CHO from meal Previous meal stimulate insulin secretion Affected by time from last meal, meal components

Intramuscular triacylglycerol (IMTG) May provide 2/3 of energy obtained from glycogen

oxidation, but precise measurement is difficult

Ex Biochem c7-lipid metabolism 55Metabolism during exercise:fat vs CHO At rest in postabsorptive state, lipid is primary fuel

source, RER~0.82 Role of exercise intensity

[FFA] increase with intensity until ~50% VO2max [glucose] increase in parallel with exercise intensity Crossover point: the relative exercise intensity at which

ATP formation from CHO exceed that of lipid Role of diet

↑muscle glycogen,↑glycogen utilization during ex Acute high-fat diet or TG infusion↑ fat use during

exercise, ↓RER High-fat diet for several days: ↑IMTG, ↑fat oxidation,

↑[FFA], ↑[glycerol] during exercise, little effect on muscle glycogen store

Ex Biochem c7-lipid metabolism 56Metabolism during exercise:fat vs CHO Medium chain TG

Exit gut into blood, no need for carnitine transport system to enter mitochondria

Most studies show no effect on endurance performance, not spare muscle glycogen or blood glucose use

Overweight and obese individuals have lower adipose tissue lipolysis and fat oxidation during exercise Blunted response to catecholamines

Compared to men, women had higher fat oxidation rate and later shift to CHO oxidation as exercise intensity increased

Ex Biochem c7-lipid metabolism 61Old theory:

FA regulate CHO metabolism


Regulation of FA oxidation in muscle

Malonyl CoA regulate FA oxidation in muscle Synthesized by acetyl CoA carboxylase (ACC-),

regulated by AMPK, glucose/insulin, and exercise ↓carnitine palmitoyl transferase I in muscle Muscle malonyl CoA↓in fasting and light exercise, ↑fat

oxidation If glucose and insulin rapidly↑, ↑malonyl CoA, ↓fat

oxidation ACC- in muscle different from ACC- in liver

Not depend on composition of diet Insensitive to insulin/glucagon Phosphorylated by AMPK inactivate ACC- Citrate a positive allosteric effector for ACC-


Skeletal, cardiac muscle

New theory:

CHO regulate FA metabolism


New theory:

CHO regulate FA metabolism


Cholesterol biosynthesis

Inhibited by Statins

Squalene synthase, Inhibited by

Lapaquistat acetate


Lipoproteins separated by centrifugation

lipid metabolism 1. ex biochem c7-lipid metabolism 2 structure of fatty acids carboxylic acid, with...

Documents