metabolism - universitas indonesiastaff.ui.ac.id/.../material/lipidmetabolism-inter08.pdf · lipid...
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Sri Widia A Jusman
Department of Biochemistry & Molecular Biology
FMUI
LIPID METABOLISM
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Lipid metabolism is concerned mainly with • fatty acids • cholesterol
Source of fatty acids• from dietary fat• de novo synthesis from acetyl CoA – derived from CH /
amino acids
Fatty acids may be• oxidized to acetyl CoA – through β-oxidation• esterified with glycerol – forming triacylglycerol (fat) – as
energy reservoir
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Acetyl CoA formed by β-oxidation
• Oxidized to CO2 + H2O via the citric acid cycle
• Precursor for synthesis of cholesterol & steroids
• Form ketone bodies in the liver – important fuel in prolong starvation
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Triacylglycerol
Fatty acids
Acetyl CoA
TCA
lipol
ysis
β-ox
idat
ion
este
rific
atio
nlip
ogee
nesi
s
CO2
Diet
Cholesterol
Ketone bodies
Steroids
CH, AA
Overview of lipid metabolism
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LIPID METABOLISM
• Lipid transport• Fatty acid metabolism (saturated &
unsaturated fatty acids) - synthesis de novo - β-oxidation• Ketogenesis• Metabolism of cholesterol
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TRANSPORT OF LIPID IN BLOOD
• transport as lipoprotein (after binding with protein) - to make more soluble in water medium ( blood) - protein consist of amino acids - contain - COOH and -NH2 group
• Lipoproteins = Lipid + Protein - triacylglycerol apoprotein - phospholipid - cholesterol
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LIPID IN BLOOD (Lipoproteins)
• Chylomicron• VLDL (very low / light density lipoprotein )• LDL (low / light density lipoprotein )• HDL ( high density lipoprotein )
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Lipid transport from intestine ( exogen lipid ) - chylomicron
• start in intestine as nascent chylomicron, particularly contain much triacylglycerol, apoB48 dan apoA ,transport in blood
• intra endhothelial cells of blood vessel - lipoprotein lipase , convert triacylglycerol (t.a.g) glycerol + fatty acids
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• fatty acid – taken up by cells - oxidized as energy ( e.g heart muscle, skeletal muscle ) or - resynthesized to t.a.g and stored in adipose tissues
• glycerol – taken up by cells - convert to glycerol 3-P - for resynthesis of t.a.g in adipose tissue
After hydrolysis of t.a.g by lipoprotein lipase - chylomicron change to chylomicron remnant - transported back to the liver
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Lipid transport from liver ( endogen lipid ) - VLDL
• from liver - transport in blood as very light density lipoprotein (VLDL) - particularly contain much t.a.g, apo B100
• intra endothelial cells of blood vessel - lipoprotein lipase, convert t.a.g fatty acid + glycerol
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• fatty acid – taken up by cells
- oxidized as energy or
- resynthesized to t.a.g, stored in adipose
tissue
• Glycerol – taken up by cells for resynthesis of t.a.g in adipose tissues
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• after release t.a.g - VLDL change to IDL (intermediate density lipoprotein), especially contain much cholesterol
• Some of IDL taken up by liver cells - metabolized in liver cells
• another part of IDL change to LDL (low density lipoprotein) – taken up by cells which need cholesterol - for membrane structure, or precursor for synthesis of steroid hormones
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• enzyme LCAT (Lecithin-Cholesterol Acyl Transferase) involve in removal of excess cholesterol from tissues - transport as HDL (high density lipoprotein) – transport back to the liver
• cholesterol excreted from liver as bile salts or resecreted as VLDL
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FFA-albumin
Postpandrial – blood level of FFA-albumin ↓
In starvation – FFA-albumin ↑
Increased of FFA-albumin blood level – marker of lipolysis ( hydrolysis of t.a.g from adipose tissue)
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DM (deficiency of insulin) • minimally glycolysis process – di-OH acetone-P ↓
- glycerol 3-P ↓ - resynthesis of t.a.g ↓ - tag were hydrolyzed - lipolysis – FFA ↑ - acyl CoA ↑ - used for energy
High fat, low carbohydrate intake • glycolysis ↓ - fatty acid in the blood can not use
for resynthesis of t.a.g – FFA ↑
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β - OXIDATION OF FATTY ACIDS
• Oxidation/breakdown of fatty acids - on β-carbon of fatty acids
• Proceed in mitochondria
• Lipid from blood (FA) - enter cells - cytosol - activated to acyl CoA - need ATP, coenzyme A
• To enter mitochondria – acyl CoA need carnitine
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• In matrix mitochondria, acyl CoA undergoes β-oxidation to produce acetyl CoA
• After each step of β-oxidation - will produced acetyl CoA + acyl CoA ( minus 2 carbon atom )
• Palmitic acid ( 16 C ) - undergo 7 X β-oxidation, produce 8 acetyl CoA
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Fatty acid
Acyl CoA
Acyl CoA
Acyl CoA (- 2 C) Acetyl CoA
TCA
CO2
β-oxidation of fatty acid
CoA ATP
Inner mitochondrial
membrane
FAD
FADH2
NAD
NADH
ATP + H2O
ATP + H2O
RC
RC
RCATP + H2O
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SYNTHESIS OF FATTY ACIDS (LIPOGENESIS)
Fatty acids - energy for heart muscle - energy reservoir in adipose tissue
Fatty acids can synthesized from glucose pyruvic acid acetyl CoA carbohydrate intake - acetyl CoA - fatty acids synthesis
Occurred in cytosol
Need - acetyl CoA - NADPH ( from HMP shunt )
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Acetyl CoA
Malonyl CoA
Palmitate
CO2
NADPH + H+
NADP+
Citrate
Citrate
Acetyl CoAPyruvate
Pyruvate
Glucose
oxaloacetate
HMP shunt
Malate DH
Isocitrate DH
MitochondriaCYTOSOL
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SOURCE of NADPH for FATTY ACID SYNTHESIS
HMP shunt tissues which are active in HMP shunt also active in
lipogenesis – liver, adipose tissue, mammary tissue during lactation, gonade
Malate dehydrogenase NADP+ NADPH + H+
malate pyruvate CO2
Isocitrate dehydrogenase NADP+ NADPH + H+
isocitrate α-ketoglutarate
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SOURCE of ACETYL CoA for FATTY ACID SYNTHESIS
→ from carbohydrate in the diet
carbohydrate ↑ - glucose ↑ - pyruvate ↑ - enter
mitochondria – acetyl CoA ↑– conjugated with
oxaloacetate – citrate – out from mitochondria – enter
cytosol – break to oxaloacetate + acetyl coA, catalyzed by
ATP-citrate lyase
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SYNTHESIS of UNSATURATED FATTY ACIDS
(MUFA ) MONOUNSATURATED FATTY ACIDS
synthesized from saturated FA by ∆9 desaturase palmitic acid palmitoleic acid 16 C 16 C : 1 stearic acid oleic acid 18 C 18 C : 1
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POLYUNSATURARATED FATTY ACIDS ( PUFA ) In human – PUFA were synthesized from MU FA,
addition of double bond occur between the existing double bond (∆9) and carboxyl group – produced ω-9
In plant – addition of double bonds also occur
between the existing double bond and the omega (ω) carbon
ω -6 : linoleic acid ( 18 C : 2) arachidonic acid ( 20 C : 3) ω -3 : linolenic acid ( 18 C : 3 ) → essential fatty acids – must present in the diet
– needed for membrane structure, component of lipoproteins, eicosanoids
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KETOGENESIS
• DM• Starvation• High fat & low carbohydrate diet → mobilization of fat from adipose tissue →
hydrolysis of t.a.g ↑ in adipose tissue → FFA ↑ in blood → enter cells - oxidized to energy via β-oxidation in mitochondria → acetyl CoA ↑ → converted to acetoacetate, β-OH butyrate & acetone in liver
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• Acetoacetate & β-OH butyrate – were used as energy for extrahepatic tissues - convert into acetyl CoA – oxidized via TCA cycle – produced ATP
• acetone - can not oxidized to produced energy – were excreted in the urine or in breath
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• N blood level of ketone bodies ≤ 1 mg / dL (= 2
mmol / L)
• If production of ketone bodies exceed the capacity of extrahepatic tissues to used it as energy → ketone bodies blood level ↑
• blood level ↑ → ketonemia - urinary excretion ↑
→ ketonuria → ketosis
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Acyl CoA
Acetyl CoA
Ketone bodies
Ketone bodies
Ketone bodies
Acetyl CoA
TCA
CO2
Urine
Lung
Liver Blood Extrahepatic tissues
FFA
Synthesis, oxidation and excretion of ketone bodies
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CHOLESTEROL METABOLISM
Cholesterol – derived from • Diet, and • Biosynthesis
Cholesterol – only produced in animal (not in plant)
Produced from acetyl CoA in liver, skin, adrenal cortex, gut, testes, aorta
Acetyl CoA is the source of all C atom in cholesterol
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Acetyl CoA
Aceto acetyl CoA
HMG CoA
Mevalonate
Squalene
Cholesterol
HMG CoA reductase
Cholesterol
Bile acid
Statin -
-
Bile acidsSteroid hormones Vitamin D
Membrane structure
Biosynthesis of cholesterol
Fatty acidCH, AA
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Cholesterol
• transported between tissues in lipoproteins• excreted in bile – as cholesterol or bile acids
(salts)
Function of cholesterol, precursor of• Steroid hormone• Vitamin D• Bile acid
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• Cholesterol in food – esterified to fatty acid
• In gut – hydrolized to free cholesterol and fatty acids – absorbed from intestine as chylomicron
• After triacylglycerol in chylomicron hydrolized by lipoprotein lipase, chylomicrom remnant particularly contain cholesterol – transport to the liver – resecreted as - VLDL
- cholesterol in bile
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• Cholesterol can synthesized in liver – secreted into blood as VLDL
• After triacylglycerol in VLDL hydrolyzed by lipoprotein lipase, VLDL remnant (= intermediate density lipoprotein, LDL) – some are transported to the liver – pathway ∼ chylomicron remnant
• Some of IDL convert to LDL – particularly contain cholesterol
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• LDL – taken up by tissue via LDL receptor - membrane structure - synthesis of hormone steroid - accumulate in tissue
• HDL – function in removal of excess cholesterol – transported back to the liver
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Serum cholesterol is correlated with incidence of atherosclerosis & coronary heart disease
Diet – important in reducing serum cholesterol
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HORMONAL INFLUENCE on LIPID MOBILIZATION
• INSULIN - inhibit activity of hormone-sensitive lipase - inhibit removal of FA (lipolysis) from adipose tissue - stimulate activity of pyruvate dehydrogenase - stimulate activity of CoA carboxylase - stimulate activity glycerol 3-P acyl transferase→ Promote lipogenesis
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• Epinephrine, norepinephrine, ACTH, MSH, TSH, GH, thyroid hormone, glucocorticoid hormone
- stimulate activity of hormone-sensitive lipase→ Promote lipolysis
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