Lipid Metabolism 1. Ex Biochem c7-lipid metabolism 2 Structure of fatty acids Carboxylic acid, with...
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Transcript of 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
Ex Biochem c7-lipid metabolism 3
n-3 (-3), n-6 (-6) fatty acids
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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
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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
Ex Biochem c7-lipid metabolism 12
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
Ex Biochem c7-lipid metabolism 13
adipocyte
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Coenzyme A
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Lipolysis
Favored under increasing energy needs Exercise, low-calorie dieting, fasting
Catalyzed by hormone-sensitive lipase In adipocyte, muscle fiber In cytosol
Ex Biochem c7-lipid metabolism 19
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 21
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
Ex Biochem c7-lipid metabolism 23
Regulation of lipolysis through HSL
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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
Ex Biochem c7-lipid metabolism 26
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
Ex Biochem c7-lipid metabolism 27
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
Ex Biochem c7-lipid metabolism 28
Recycling of TAG in adipocyte
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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)
Ex Biochem c7-lipid metabolism 31
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 32
Ex Biochem c7-lipid metabolism 33FA transport through mitochondrial membrane
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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
Ex Biochem c7-lipid metabolism 38
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
Ex Biochem c7-lipid metabolism 39
Ketone bodies
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Formation of ketone bodies
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Formation of acetoacetate
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Ketone bodies as fuel for mitochondria
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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
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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
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--+
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Triacylglyceride synthesis
Ex Biochem c7-lipid metabolism 50FA do not form glucose
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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
Ex Biochem c7-lipid metabolism 52
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 53
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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
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Ex Biochem c7-lipid metabolism 60
Ex Biochem c7-lipid metabolism 61Old theory:
FA regulate CHO metabolism
Ex Biochem c7-lipid metabolism 62
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-
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Skeletal, cardiac muscle
New theory:
CHO regulate FA metabolism
Ex Biochem c7-lipid metabolism 66
New theory:
CHO regulate FA metabolism
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Cholesterol biosynthesis
Inhibited by Statins
Squalene synthase, Inhibited by
Lapaquistat acetate
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Lipoproteins separated by centrifugation