LIPID METABOLISM Sri Widia A Jusman Department of Biochemistry & Molecular Biology FMUI
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 CO 2 + H 2 O via the citric acid cycle Precursor for synthesis of cholesterol & steroids Form ketone bodies in the liver important fuel in prolong starvation
esterification Triacylglycerol lipolysis Steroids Diet lipogeenesis Fatty acids β-oxidation CH, AA Acetyl CoA Cholesterol TCA Ketone bodies Overview of lipid metabolism CO2
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, apob 48 dan apo A, 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 B 100 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
CoA Fatty acid ATP Acyl CoA Acyl CoA FAD FADH2 RC Inner mitochondrial membrane ATP + H2O NAD NADH RC ATP + H2O Acyl CoA (- 2 C) Acetyl CoA TCA RC ATP + H2O β-oxidation of fatty acid CO 2
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 )
Glucose Palmitate NADP + HMP shunt Malate DH Isocitrate DH NADPH + H + Malonyl CoA Pyruvate Citrate CO2 Acetyl CoA Pyruvate Acetyl CoA oxaloacetate Citrate Mitochondria CYTOSOL
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 CO 2 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
Liver Blood Extrahepatic tissues Acyl CoA FFA Acetyl CoA Urine Ketone bodies Ketone bodies Ketone bodies Acetyl CoA Lung TCA Synthesis, oxidation and excretion of ketone bodies CO 2
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
CH, AA Fatty acid Acetyl CoA Aceto acetyl CoA Statin - HMG CoA HMG CoA reductase Mevalonate - Biosynthesis of cholesterol Squalene Cholesterol Bile acid Cholesterol Bile acids Steroid hormones Vitamin D Membrane structure
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