Upload
others
View
16
Download
0
Embed Size (px)
Citation preview
Sri Widia A Jusman
Department of Biochemistry & Molecular Biology
FMUI
LIPID METABOLISM
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
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
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
LIPID METABOLISM
• Lipid transport• Fatty acid metabolism (saturated &
unsaturated fatty acids) - synthesis de novo - β-oxidation• Ketogenesis• Metabolism of cholesterol
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
LIPID IN BLOOD (Lipoproteins)
• Chylomicron• VLDL (very low / light density lipoprotein )• LDL (low / light density lipoprotein )• HDL ( high density lipoprotein )
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
• 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
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
• 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
• 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
• 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
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)
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 ↑
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
• 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
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
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 )
Acetyl CoA
Malonyl CoA
Palmitate
CO2
NADPH + H+
NADP+
Citrate
Citrate
Acetyl CoAPyruvate
Pyruvate
Glucose
oxaloacetate
HMP shunt
Malate DH
Isocitrate DH
MitochondriaCYTOSOL
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
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
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
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
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
• 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
• 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
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
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
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
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
• 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
• 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
• 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
Serum cholesterol is correlated with incidence of atherosclerosis & coronary heart disease
Diet – important in reducing serum cholesterol
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
• Epinephrine, norepinephrine, ACTH, MSH, TSH, GH, thyroid hormone, glucocorticoid hormone
- stimulate activity of hormone-sensitive lipase→ Promote lipolysis