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