Lipid Metabolism
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Ex Biochem c7-lipid metabolism
Structure of fatty acids
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Carboxylic acid, with long alkyl chain
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Saturated, monounsaturated (MUFA),
polyunsaturated (PUFA)
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Short chain: 4-6 carbons
Medium chain: 8-12 carbons
Long chain: 14 or more carbons
Double bonds always in cis formation
Usually use common name or abbreviation
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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
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Ex Biochem c7-lipid metabolism
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Ex Biochem c7-lipid metabolism
n-3 (w-3), n-6 (w-6) fatty acids
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Ex Biochem c7-lipid metabolism
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Ex Biochem c7-lipid metabolism
Types of lipids
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Triacylglycerol, triglyceride
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Glycerol + 3 fatty acids (saturated or unsaturated)
Also diacylglycerol, monoacylglycerol
Structure of FAs decide physical and physiological
functions of TG
Phospholipids
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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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Ex Biochem c7-lipid metabolism
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Ex Biochem c7-lipid metabolism
Fat stores
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FA obtained mainly from food fat
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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
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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
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Ex Biochem c7-lipid metabolism
Formation of TAG
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Fat synthesis is favored following a meal
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FA must be activated by attaching to CoA
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Acyl CoA synthetase
Glycerol 3-phosphate from glycolysis
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Stimulated by insulin
In cytosol
From dihydroxyacetone phosphate by glycerol phosphate
DHase (in glycerol phosphate shuttle)
Acyl transfer to glycerol-3-P
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Glycerol phosphate acyltransferase to form phosphatidate
Phosphatidate phosphatase, then add another FA
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Ex Biochem c7-lipid metabolism
adipocyte
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Ex Biochem c7-lipid metabolism
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Ex Biochem c7-lipid metabolism
Coenzyme A
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Ex Biochem c7-lipid metabolism
Lipolysis
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Favored under increasing energy needs
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Exercise, low-calorie dieting, fasting
Catalyzed by hormone-sensitive lipase
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In adipocyte, muscle fiber
In cytosol
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Ex Biochem c7-lipid metabolism
Lipolysis
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Ex Biochem c7-lipid metabolism
Regulation of TAG turnover
in adipocyte
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Lipid droplets surrounded by perilipins
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A protein family, make lipid droplet inaccessible to HSL
Epinephrine, norepinephrine↑lipolysis, insulin↓lipolysis
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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
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Ex Biochem c7-lipid metabolism
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Ex Biochem c7-lipid metabolism
Regulation of TAG turnover
in muscle fiber
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Theoretically, TAG synthesis and lipolysis can be
fully active at the same time in muscle and
adipocyte
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Muscle HSL regulated similar to adipocyte
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Although usually one is favored the other
No perilipin in skeletal muscle
Other regulatory factors in muscle fiber
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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
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Ex Biochem c7-lipid metabolism
Regulation of lipolysis through HSL
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Ex Biochem c7-lipid metabolism
Fate of FA and glycerol
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TAG-FA cycle
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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
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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 reesterification
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Ex Biochem c7-lipid metabolism
Fate of FA and glycerol
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Glyceroneogenesis
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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
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High glycerol kinase activity
Glycerol important source for gluconeogenesis during
fasting/starvation
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Ex Biochem c7-lipid metabolism
Fate of FA and glycerol
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Free fatty acid (FFA)
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FFA taken up by liver, re-esterification
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VLDL, LPL, FA into adipocyte, incorporated into TAG and stored
High blood [FFA] in obesity
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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
In obese individuals, cause insulin resistance
Thiazolidinediones (TZDs) ↓blood [FFA], ↓insulin
resistance
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Agonist for peroxisome proliferator-activated receptor g (PPAR- g)
Control glycerol kinase, PEPCK in adipocyte
↑glycerol 3-P synthesis, ↑re-esterification of FA
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Ex Biochem c7-lipid metabolism
Recycling of TAG in adipocyte
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Ex Biochem c7-lipid metabolism
Oxidation of FA
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Intracellular transport of FA
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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)
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Ex Biochem c7-lipid metabolism
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Oxidation of FA
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Transport as acylcarnitine 肉鹼
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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
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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
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Ex Biochem c7-lipid metabolism
FA transport through
mitochondrial membrane
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Ketone bodies 酮體
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Water-soluble energy-providing lipids
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Acetoacetate, D-3-hydroxybyturate, acetone
Formation accelerated when CHO content and
insulin is extremely low
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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
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Ex Biochem c7-lipid metabolism
Ketone bodies
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Used as fuel for mitochondria in extrahepatic tissues
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Ketosis: prolonged depletion of body CHO, uncontrolled
DM
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Skeletal muscle, heart, brain
When glucose unavailable
Ketonemia, ketonuria, acetone breath, elevated blood [FFA],
acidosis
Benefit for exercise?
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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
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Ex Biochem c7-lipid metabolism
Ketone bodies
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Ex Biochem c7-lipid metabolism
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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Ex Biochem c7-lipid metabolism
Synthesis of fatty acids
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Most FA used by humans come from dietary fat
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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
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Start with 3-carbon malonyl CoA
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Ex Biochem c7-lipid metabolism
Synthesis of fatty acids
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Continuous supply of acetyl CoA in cytosol
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Supply of NADPH
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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)
Pentose phosphate pathway
Malic enzyme
Malate + NADP > pyruvate + CO2 + NADPH + H+
Fatty acid synthase: large enzyme contain 7 distinct
enzyme activities
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Acyl carrier protein
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Triacylglyceride synthesis
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FA do not form
glucose
Ex Biochem c7-lipid metabolism
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Ex Biochem c7-lipid metabolism
Regulation of FA synthesis
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DNL minor to overall energy balance in average person on
typical mixed diet
Acetyl CoA carboxylase key site for regulation
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Dietary control
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high-CHO diet↑expression of ACC, FAS
high-fat diet↓expression of ACC, FAS
insulin↑de novo lipogenesis
Malonyl CoA inhibit CPT1
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↑by citrate, ↓by fatty acyl CoA, malonyl CoA
Inhibited by PKA and AMPK (AMPK activated by↑AMP)
Phosphorylation/dephosphorylation depend on insulin/glucagon
↓FA oxidation in mitochondria
People become obese when excess food intake
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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
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Ex Biochem c7-lipid metabolism
Fat as fuel for exercise
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Plasma FFA gradually increase during prolonged
exercise
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Lower [FFA] during exercise in fed state
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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
Greater oxidation of CHO from meal
Previous meal stimulate insulin secretion
Affected by time from last meal, meal components
Intramuscular triacylglycerol (IMTG)
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May provide 2/3 of energy obtained from glycogen
oxidation, but precise measurement is difficult
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Ex Biochem c7-lipid metabolism
Metabolism during exercise:
fat vs CHO
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At rest in postabsorptive state, lipid is primary fuel
source, RER~0.82
Role of exercise intensity
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[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
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↑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
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Ex Biochem c7-lipid metabolism
Metabolism during exercise:
fat vs CHO
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Medium chain TG
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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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Old theory:
FA regulate CHO metabolism
Ex Biochem c7-lipid metabolism
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Ex Biochem c7-lipid metabolism
Regulation of FA oxidation in muscle
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Malonyl CoA regulate FA oxidation in muscle
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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
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Not depend on composition of diet
Insensitive to insulin/glucagon
Phosphorylated by AMPK inactivate ACC-b
Citrate a positive allosteric effector for ACC-b
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New theory:
CHO regulate FA metabolism
Skeletal,
cardiac
muscle
Ex Biochem c7-lipid metabolism
New theory:
CHO regulate FA metabolism
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Ex Biochem c7-lipid metabolism
Cholesterol biosynthesis
Inhibited
by Statins
Squalene synthase,
Inhibited by
Lapaquistat acetate
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Ex Biochem c7-lipid metabolism
Lipoproteins
separated by
centrifugation
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