Lipid Metabolism.

Name: Lipid Metabolism.
Uploaded: 2017-08-24T11:50:13+00:00
Duration: PTM25S27
Channel: Aron Leonard
Description: Lipid Metabolism.

Lipid Metabolism

Structure of fatty acids
Ex Biochem c7-lipid metabolism 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 w-3) and n-6 (or w-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

Ex Biochem c7-lipid metabolism

n-3 (w-3), n-6 (w-6) fatty acids
Ex Biochem c7-lipid metabolism n-3 (w-3), n-6 (w-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

Regulation of TAG turnover in adipocyte
Ex Biochem c7-lipid metabolism Regulation of TAG turnover in 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

Regulation of TAG turnover in muscle fiber
Ex Biochem c7-lipid metabolism Regulation of TAG turnover in 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
Ex Biochem c7-lipid metabolism Regulation of lipolysis through HSL

Fate of FA and glycerol TAG-FA cycle Continuous 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 g (PPAR- g) Control glycerol kinase, PEPCK in adipocyte ↑glycerol 3-P synthesis, ↑re-esterification of FA

Recycling of TAG in adipocyte
Ex Biochem c7-lipid metabolism 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

FA transport through mitochondrial membrane
Ex Biochem c7-lipid metabolism FA 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
Ex Biochem c7-lipid metabolism Formation of ketone bodies

Formation of acetoacetate
Ex Biochem c7-lipid metabolism Formation of acetoacetate

Ketone bodies as fuel for mitochondria
Ex Biochem c7-lipid metabolism Ketone bodies as fuel for mitochondria

Synthesis of fatty acids
Ex Biochem c7-lipid metabolism 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
Ex Biochem c7-lipid metabolism 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 Triacylglyceride synthesis

FA do not form glucose

Regulation of FA synthesis
Ex Biochem c7-lipid metabolism 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
Ex Biochem c7-lipid metabolism 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

Metabolism during exercise: fat vs CHO
Ex Biochem c7-lipid metabolism Metabolism 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

Metabolism during exercise: fat vs CHO
Ex Biochem c7-lipid metabolism Metabolism 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

Old theory: FA regulate CHO metabolism

Regulation of FA oxidation in muscle
Ex Biochem c7-lipid metabolism Regulation of FA oxidation in muscle Malonyl CoA regulate FA oxidation in muscle Synthesized by acetyl CoA carboxylase b(ACC-b), 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-b in muscle different from ACC-a in liver Not depend on composition of diet Insensitive to insulin/glucagon Phosphorylated by AMPK inactivate ACC-b Citrate a positive allosteric effector for ACC-b

New theory: CHO regulate FA metabolism Skeletal, cardiac muscle

New theory: CHO regulate FA metabolism

Cholesterol biosynthesis
Ex Biochem c7-lipid metabolism Cholesterol biosynthesis Inhibited by Statins Squalene synthase, Inhibited by Lapaquistat acetate

Lipoproteins separated by centrifugation
Ex Biochem c7-lipid metabolism Lipoproteins separated by centrifugation

Lipid Metabolism.

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