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Chapter 5 Metabolism of Lipids The biochemistry and molecular biology department of CMU Concept • Lipids are substances that are insoluble or immiscible in water, but soluble in organic solvents. Fats (Triglyceride or triacylglycerole) To store and supply energy Lipids Phospholipids Glycolipids Lipoids Cholesterol Cholesterol ester To be important membrane components Contents Section 1 Fatty acids Section 2 Metabolism of Triglycerids Section 3 Metabolism of Phospholipids Section 4 Metabolism of Cholesterols Section 5 Metabolism of Plasma Lipoproteins Section 1 Fatty acids §1.1 Classification of fatty acids Numerical Symbol Common Name Comments 14:0 Myristic acid Saturated 16:0 Palmitic acid Saturated 18:0 Stearic acid Saturated 16:1 Δ 9 Palmitoleic acid Unsaturated 18:1 Δ 9 Oleic acid Unsaturated 18:2 Δ 9,12 Linoleic acid EFA 18:3 Δ 9,12,15 Linolenic acid EFA 20:4 Δ 5,8,11,14 Arachidonic acid EFA Essential Fatty Acids (EFA) • Linoleic, linolenic and arachidonic acids are called essential fatty acids, because they cannot be synthesized by the body and must be obtained through diet. §1.2 Important Derivatives of Arachidonic acids Arachidonic acids (AA) in turn gives rise to biologically important substances known as the eicosanoids. • Prostaglandins (PGs) • Thromboxanes (TXs) • Leukotrienes (LTs) Section 2 Metabolism of Triglycerides Triglyceride (TG) or triacylglycerol (TAG) Glycerol O O 1 CH2 O C R1 2 R2 C O C H 3 O CH2 O C R3 Overview of triglycerides metabolism Triglycerides (fats) Lipolysis Esterification Diet Fatty acids Lipogenesis Carbohydrate Amino acids Steroids ¦Â-Oxidation Steroidogenesis Acetyl-CoA Cholesterol CholesteroloKe genesis tog en es TAC is Ketone bodies 2CO2 § 2.1 Degradation of TG § 2.1.1 Fat catabolism (lipolysis) § 2.1.2 β-Oxidation of Fatty acids § 2.1.3 Other Oxidations of Fatty acids § 2.1.4 Ketone Bodies Formation and Utilization § 2.1.1 Fat catabolism (lipolysis) Fat mobilization: The triacylglycerol stored in the adipocytes are hydrolyzed by lipases, to produce free fatty acids (FFA) and glycerol, which are released to the blood, this process is called fat mobilization. The fatty acids thus released diffusively from the adipocyte into the blood, where they bind to the serum albumin. Hormone sensitive lipase (HSL) • TG lipase is the rate-limiting enzyme in the TG degradation in adipose tissue. It is also named HSL because it is regulated by some hormones. Effect of hormones on lipolysis • Lipolytic Hormones: epinephrine norepinephrine adrenocorticotropic hormone (ACTH) thyroid stimulating hormone (TSH) Glucagon etc. • Antilipolytic Hormones: insulin glycerol metabolism Place: liver, kidney, intestine g ADP CH2OH CH2OH ATP 3-phlycerol deh osph yd r o HO C H a HO C H g en t e glycerol as e CH2O P kinase CH2OH NAD+ CH2OH Glycerol L-Glycerol 3-phosphate O C NADH+H+ Glycolysis CHO H C OH Glyconeogenesis CH2O P D-Glyceraldehyde 3-phosphate CH2O P Dihydroxyacetone triose phosphate phosphate isomerase Note • In muscle cells and adipocytes, the activity of glycerol kinase is low, so these tissues cannot use glycerol as fuel. § 2.1.2 β-Oxidation of Fatty acids • Fatty acids are one of the main energy materials of human and other mammalian. • Fatty acid catabolism can be subdivided into 3 stages. Stage 1 Activation of FAs • Acyl-CoA Synthetase (Thiokinase), which locates on the cytoplasm, catalyzes the activation of long chain fatty acids. O R C + HSCoA O Fatty acid AMP + PPi O Mg2+ R C acyl-CoA S CoA synthetase acyl-CoA ATP Key points of FA activation 1. Irreversible 2. Consume 2 ~P 3. Site: cytosol Stage 2 Transport of acyl CoA into the mitochondria ( rate-limiting step) • Carrier: carnitine Rate-limiting enzyme • carnitine acyltransferase Ⅰ CH3 OH + H3C N CH2 CH CH2 COO CH3 Carnitine CH3 + H3C N CH2 CH3 C O SCoA carnitine acyltransferase ¢ñ R C R O O CH CH2 COO Fatty acyl carnitine HSCoA Stage 3: β-oxidation of FAs β-oxidation means β-C reaction. Four steps in one round step 1: Dehydrogenate step 2: Hydration step 3: Dehydrogenate step 4: Thiolytic cleavage Step 1. Dehydrogenate H3C H H O C C C H FAD H (CH2)n SCoA Fatty acyl-CoA acyl-CoA dehydrogenase FADH2 H3C (CH2)n C H H O C C SCoA trans-¦¤2-enoyl-CoA Step 2. Hydration H3C (CH2)n C H O C C Trans-¦¤2-enoyl-CoA H H2 O H3C (CH2)n SCoA enoyl-CoA Hydratase OH H O C C C H H 3-L-Hydroxyacyl-CoA SCoA Step 3. Dehydrogenate H3C OH H O C C C H NAD+ H 3-L-Hydroxyacyl-CoA (CH2)n NADH + H+ hydroxyacyl-CoA dehydrogenase O H3C (CH2)n C SCoA O CH2 C SCoA β-Ketoacyl-CoA Step 4. Thiolytic cleavage O H3C (CH2)n C O CH2 C SCoA β-Ketoacyl-CoA HSCoA β-Ketothiolase O H3C (CH2)n C O SCoA + CH3 Fatty acyl-CoA (2C shorter) C SCoA Acetyl-CoA β- oxidation of fatty acids The β-oxidation pathway is cyclic Summary one cycle of the β-oxidation: fatty acyl-CoA + FAD + NAD+ + HS-CoA →fatty acyl-CoA (2 C less) + FADH2 + NADH + H+ + acetyl-CoA The product of the β-oxidation is in the form of FADH2, NADH, acetyl CoA, only after Krebs cycle and oxidative phosphorylation, can ATP be produced. Energy yield from one molecule of palmitic acid palmitic acid -2 ~P activation 7¡Á 2 respiratory chain 8 acetyl CoA + 7 FADH2 + 7 NADH + 7 H+ palmitoyl-CoA 7 turns of ¦Â-oxidation TAC respiratory chain 8¡Á 12 7¡Á 3 The net ATP production: 131-2 = 129 § 2.1.3 Other Oxidations of Fatty acids 1. Oxidation of unsaturated fatty acids 2. Peroxisomal fatty acid oxidation 3. Oxidation of propionyl-CoA 1. Oxidation of unsaturated fatty acid • Mitochondria • Isomerase: cis → trans • Epimerase: D (-) → L (+) 2. Peroxisomal fatty acid oxidation Very long chain fatty acids FAD Acyl-CoA oxidase shorter chain fatty acids β-oxidation 3. Oxidation of propionyl-CoA propionyl-CoA Carboxylase (biotin) Epimerase Mutase (VB12) succinyl-CoA § 2.1.4 Ketone Bodies Formation and Utilization • Ketone bodies are water-soluble fuels normally exported by the liver but overproduced during fasting or in untreated diabetes mellitus, including acetoacetate, βhydroxybutyrate, and acetone. The formation of ketone bodies (Ketogenesis) Location: hepatic mitochondria Material: acetyl CoA Rate-limiting enzyme: HMG-CoA synthase O CH3 C S CoA HSCoA O + CH3 2 Acetyl-CoA O CH3 C S CoA thiolase O C CH2 C S CoA Acetoacetyl-CoA HMG-CoA synthase OH OH CH3 OOC CH2 CH CH2 COO HSCoA O C CH2 C S CoA CH3 ¦Â-Hydroxy-¦Â-methylglutaryl-CoA ¡¡ ¡¡ ¡¡ ¡¡ £¨ HMG-CoA£© ¦Â-Hydroxy-butyrate NAD+ ¦Â-hydroxybutyrate dehydrogenase NADH+H+ HMG-CoA lyase O Acetyl-CoA O CH3 C CH3 Acetone Acetyl-CoA CH3 CO2 C CH2 COO Acetoacetate Utilization of ketone bodies (ketolysis) at extrahepatic tissues Succinyl-CoA transsulfurase HSCoA ATP - AMP PPi Acetoacetate thiokinase Lack of succinyl-CoA transsulfurase and Acetoacetate thiokinase in the liver. Biological Significance • Ketone bodies replace glucose as the major source of energy for many tissues especially the brain, heart and muscles during times of prolonged starvation. Normal physiological responses to carbohydrate shortages cause the liver to increase the production of ketone bodies from the acetyl-CoA generated from fatty acid oxidation. Hepatocyte Acetoacetate, β-hydroxybutyrate, acetone Ketone body formation Fatty Acetyl-CoA acids β-oxidation CoA Citric Acid cycle Ketone bodies exported as energy source for heart, skeletal muscle, kidney, and brain oxaloacetate gluconeogenesis Glucose Glucose exported as fuel for tissues such as brain Plasma concentrations of metabolic fuels (mmol/L) in the fed and starving states Ketosis consists of ketonemia, ketonuria and smell of acetone in breath Causes for ketosis • Severe diabetes mellitus • Starvation • Hyperemesis (vomiting) in early pregnancy § 2.2 Lipogenesis § 2.2.1 Synthesis of fatty acid O C-S-CoA H3C palmitic acid (C16:0) palmitoylCoA O C-S-CoA H3C stearic acid (C18:0) stearoylCoA O C-S-CoA 9 oleic acid (C18:1 D9) 18 H3C 1 oleoylCoA 1. Palmitic Acid Synthesis Location: cytosol of liver, adipose tissue, kidney, brain and breast. Precursor: acetyl CoA Other materials: ATP, NADPH, CO2 Citrate-pyruvate cycle mitochondrion Acetyl CoA citrate TCAC cytosol Acetyl CoA citrate oxaloacetate NADH oxaloacetate malate malate NADPH pyruvate pyruvate CO2 glucose The sources of NADPH are as follows: • Pentose phosphate pathway • Malic enzyme • Cytoplasmic isocitrate dehydrogenase Process of synthesis: (1) Carboxylation of Acetyl CoA (2) Repetitive steps catalyzed by fatty acid synthase (1) Carboxylation of Acetyl CoA O CH3 C SCoA + HCO3 acetyl-CoA ATP ADP + Pi biotin acetyl-CoA carboxylase O OOC CH2 C SCoA malonyl-CoA Malonyl-CoA serves as the donor of twocarbon unit. Acetyl-CoA Carboxylase is the rate limiting enzyme of the fatty acid synthesis pathway. The mammalian enzyme is regulated, by phosphorylation allosteric regulation by local metabolites. glucagon ATP insulin ADP + Pi acetyl-CoA + HCO3 + H+ malonyl-CoA acetyl-CoA carboxylase (biotin) long chain acyl-CoA citrate isocitrate (2) Repetitive steps catalyzed by fatty acid synthase Fatty acid synthesis from acetyl-CoA & malonyl-CoA occurs by a series of reactions that are: in bacteria catalyzed by seven separate enzymes. in mammals catalyzed by individual domains of a single large polypeptide. Fatty acid synthase complex (multifunctional enzyme) • • • • • • • • Acyl carrier protein (ACP) Acetyl-CoA-ACP transacetylase (AT) β-Ketoacyl-ACP synthase (KS) Malonyl-CoA-ACP transferase (MT) β-Ketoacyl-ACP reductase (KR) β-Hydroacyl-ACP dehydratase (HD) Enoyl-ACP reductase (ER) Thioesterase (TE) AT MT HD Cys Subunit division HS HS KR ACP Functional division KS ER TE PhP HS HS PhP Cys TE KS ACP KR ER HD MT AT ACP contains 4’-phosphopantotheine. O HS CH3 C S CH 3 C S CoA O HS HS ACP-HS KS-HS OOC CH 2 C S CoA O HS CoA O MT AT HS CoA OOC CH2 C S CH3 C S O O CH3 (CH2)14 C O O (After 7 rounds) HS CH3 CH2 CH2 C S TE H2O ① condensation KS CO 2 O O CH3 C CH2 C S HS O AT CH3 CH2 CH2 C S HS ② ④ O reduction NADP+ CH3 CH CH2 C S HS OH ER O NADPH + H+ CH3 CH CH C S HS reduction ③ dehydration HD H2O KR NADPH + H+ NADP+ The overall reaction of synthesis: acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14H+ palmitate + 7 CO2 + 14 NADP+ + 8 HSCoA + 6H2O Differences in the oxidation and synthesis of FAs β-oxidation Fatty acid synthesis Site Mitochondria Cytoplasm Intermediates Present as CoA derivatives Covalently linked to SH group of ACP Enzymes Present as independent proteins Multi-enzyme complex Sequential units 2 carbon units split off 2 carbon units added, as 3 as acetyl CoA carbon malonyl CoA Co-enzymes NAD+ and FAD are reduced NADPH used as reducing power Routes of synthesis of other fatty acids 2. Elongation of palmitate Elongation beyond the 16-C length of the palmitate occurs in mitochondria and endoplasmic reticulum (ER). Fatty acid elongation within mitochondria uses the acetyl-CoA as donor of 2-carbon units and NADPH serves as electron donor for the final reduction step. Fatty acids esterified to coenzyme A are substrates for the ER elongation machinery, which uses malonyl-CoA as donor of 2-carbon units. 3. The synthesis of unsaturated fatty acid • Formation of a double bond in a fatty acid involves several endoplasmic reticulum membrane proteins in mammalian cells O 10 9 oleate 18:1 cis D9 C OH Desaturases introduce double bonds at specific positions in a fatty acid chain. § 2.2.2 Synthesis of Triacylglycerol • Monoacylglycerol pathway (small intestine) • Diacylglycerol pathway (liver, adipose tissue) 1. Monoacylglycerol pathway O O CH2 HSCoA OH acyl CoA R2 C O C H CH2 OH acyl CoA transferase O CH2 R2 C O C H CH2 O acyl CoA transferase C R1 OH 1,2-diacylglycerol 2-monoacylglycerol HSCoA acyl CoA O O CH2 O C R1 R2 C O C H O CH2 O C R3 triacylglycerol 2. Diacylglycerol pathway glycolysis Summary • Places: tissue small intestine, liver, adipose • Materials: Endogenous: glucose、amino acid、 glycerol Exogenous: free fatty acid and monoacylglycerol Adipose tissue generate fat mainly from glucose • In adipose tissue, the acetyl CoA for the synthesis of fatty acid is mainly from glucose. • The lack of glycerol kinase make the only source of glycerol 3-phosphate in adipose tissue is glucose. Obesity results from an imbalance between energy input and output Food adipose tissue Work or Growth fatty acids & triacylglcerols ADP ATP Heat CO2 + H2O Obesity Section 3 Metabolism of Phospholipids • Phospholipid refers to phosphorouscontaining lipids. Glycerophospholipids Phospholipids Sphingolipids § 3.1 Classification and Structure of Glycerophospholipids • Glycerophospholipids are lipids with a glycerol, fatty acids, a phosphate group and a nitrogenous base. glycerol fatty acids nitrogenous base Phosphatidylcholine 甘油 glycerol 脂酰基 CH2 O O R2 C O O fatty acyl group C CH2 H C R1 脂酰基 fatty acyl group O O P 含氮化合物 O X Nitrogenous base OH The basic structure of glycerophospholipid In general, glycerophospholipids contain a saturated fatty acid at C-1 and an unsaturated fatty acid (usually arachidonic acid) at C-2. The major function of phospholipids is to form biomembrane. • Hydrophobic tail = fatty acids • Polar head = nitrogenous base Some common glycerophospholipid Some common glycerophospholipid (continue) § 3.2 Synthesis of Glycerophospholipid Location: All tissue of body, especially liver & kidney Endoplasmic reticulum Pathways: CDP-diacylglycerol pathway Diacylglycerol pathway The system of synthesis a. FA Glycerol from carbohydrate b. poly unsaturated fatty acid from plant oil c. choline ethanolamine serine inositol from food or synthesis in body d. ATP, CTP e. Enzymes and cofactors Diacylglycerol pathway CO2 HO CH2 CH COOH HO CH2 CH2 NH2 3 SAM HO CH2 CH2 N(CH3)3 Choline Ethanolamine NH2 Serine ATP ATP ADP ADP P O CH2 CH2 N(CH3)3 P O CH2 CH2 NH2 Phosphocholine Phosphoethanolamine CTP CTP PPi PPi CDP O CH2 CH2 NH2 CDP O CH2 CH2 N(CH3)3 CDP-choline CDP-ethanolamine CO2 Phosphatidyl serine DG DG CMP CMP Phosphatidyl ethanolamine 3 SAM Phosphatidyl choline CDP-Diacylglycerol pathway Dihydroxyacetone phosphate Glycerol 3-phosphate Phosphotidate CTP G PPi CDP-diacylglycerol Inositol CMP Serine Phosphatidyl glycerol CMP CMP Phosphatidyl inositol Diphosphatidyl glycerol (cardiolipin) Phosphatidyl serine Phosphatidylcholine (Lecithin) Phosphatidylethanolamine (Cephalin) CDP-diacylglycerol Phosphatidylserine Phosphatidylglycerol Diphosphatidyl glycerol (Cardiolipin) Phosphatidylinositol § 3.3 Degradation of glycerophospholipids by phospholipase A1 O A2 O R2 C O O CH2 C CH2 C R1 D H O O P OH C O X O O CH2 HO C CH2 H C R1 R2 B1 O O P O OH Lysophospholipid-1 X C OH CH2 O O B2 C CH2 H O O P OH Lysophospholipid-2 O X Actions of phospholipases on lecithin • PLA1: fatty acid + lysolecithin • PLA2: fatty acid + acyl glycerophosphoryl choline • PLC: 1,2 diacylglycerol + phosphoryl choline • PLD: phosphatidic acid + choline Lysophospholipids, the products of Phospholipase A hydrolysis, are powerful detergents. O O O R2 C CH2 O C H O C R1 H2O R2 P O phospholipid O CH2 HO O PLA2 CH2O C O O X C O H O CH2O P C R1 O X O Lysophospholipid Section 4 Metabolism of Cholesterol § 4.1 Structure and function of cholesterol 1. Function of cholesterol: (1) It is a constituent of all cell membranes. (2) It is necessary for the synthesis of all steroid hormones, bile salts and vitamin D. 2. Structure of cholesterol All steroids have cyclopentano penhydro phenanthrene ring system. H3C 21 22 18 CH3 12 19 CH3 1 2 HO 4 C 9 10 A 3 11 5 B 8 6 7 23 24 25 CH3 20 27 CH3 17 13 D 16 14 15 26 Cholesterol ester O C R O § 4.2 Synthesis of cholesterol Location: • All tissue except brain and mature red blood cells. • The major organ is liver (80%). • Enzymes locate in cytosol and endoplasmic reticulum. Materials: Acetyl CoA, NADPH(H+), ATP Acetyl-CoA is the direct and the only carbon source. Acetyl-CoA HMG-CoA Acetoacetyl-CoA HMG CoA reductase is the rate-limiting enzyme The total process of cholesterol de novo synthesis Regulation of cholesterol synthesis fasting HMG CoA Glucagon HMG CoA reductase after meal insulin MVA thyroxine cholesterol bile acid § 4.3 Transformation and excretion of cholesterol Bile acids Steroid hormones Vitamin D Cholesterol 1. Conversion of Cholesterol into bile acid (1) Classification of bile acids The primary bile acids are synthesized in the liver from cholesterol. The 7hydroxylase is rate-limiting enzyme in the pathway for synthesis of the bile acids. The secondary bile acids are products that the primary bile acids in the intestine are subjected to some further changes by the activity of the intestinal bacteria. Classification of bile acids Classification Free bile acids Cholic acid Glycocholic acid Taurocholic acid Chenodeoxycholic acid Glycochenodeoxycholic acid Taurochenodeoxycholic acid Deoxycholic acid Glycodeoxycholic acid Taurodeoxycholic acid Lithocholic acid Glycolithocholic acid Taurolitho-cholic acid Primary bile acids Secondary bile acids Conjugated bile acids (2) Strcture of bile acids OH COOH COOH 12 3 HO 7 H cholic acid OH OH HO H OH glycocholic acid HO OH H chenodeoxycholic acid CONHCH2COOH HO OH H CONHCH2CH2SO3H OH taurocholic acid OH HO H deoxycholic acid COOH COOH HO H lithocholic acid (3) Enterohepatic Cycle of bile acids Conversion to bile salts, that are secreted into the intestine, is the only mechanism by which cholesterol is excreted. Most bile acids are reabsorbed in the ileum , returned to the liver by the portal vein, and re-secreted into the intestine. This is the enterohepatic cycle. (4) Function of bile acids Bile acids are amphipathic, with detergent properties. • Emulsify fat and aid digestion of fats & fat-soluble vitamins in the intestine. • Increase solubility of cholesterol in bile. 2. Conversion of cholesterol into steroid hormones • Tissues: adrenal cortex, gonads • Steroid hormones: cortisol (glucocorticoid), corticosterone and aldosterone (mineralocorticoid), progesterone, testosterone, and estradiol Steroids derived from cholesterol 3. Conversion into 7-dehydrocholesterol cholesterol £¨ in skin£© 25-hydroxylase (microsome in the liver) ultraviolet light 7-dehydrocholecalciferol (VD3) cholesterol 25-OH-D3 1¦Á-hydroxylase (mitochondria in the kidney) 1,25-(OH)2-D3 £¨ active Vit D3£© § 4.4 Esterification of cholesterol • in cells SHCoA acyl CoA O HO cholesterol acyl CoA cholesterol R C O acyl transferase cholesteryl ester (ACAT) in plasma Section 5 Plasma lipoprotein § 5.1 blood lipid • Concept: All the lipids contained in plasma, including fat, phosphalipids, cholesterol, cholesterol ester and fatty acid. • Blood lipid exist and transport in the form of lipoprotein. TG cholesterol blood lipids free ester lecithin phospholipids sphingolipids cephalin FFA § 5.2 Classification of plasma lipoproteins 1. electrophoresis method: - Lipoprotein fast pre -Lipoprotein -Lipoprotein CM (chylomicron) slow 2. Ultra centrifugation method: high density lipoprotein (HDL) high low density lipoprotein ( LDL) very low density lipoprotein ( VLDL) CM (chylomicron ) low electron microscope CM LDL VLDL HDL - + Origin CM Pre- Separation of plasma lipoproteins by electrophoresis on agarose gel § 5.3 Structure § 5.4 Composition of lipoprotein CM VLDL LDL HDL <1.006 0.951.006 1.0061.063 1.0631.210 Protein 2 10 23 55 Phospholipids 9 18 20 24 Cholesterol 1 7 8 2 Cholesteryl esters 3 12 37 15 TG 85 50 10 4 Density(g/ml) § 5.5 Apolipoproteins Functions of apolipoproteins a . To combine and transport lipids. b . To regulate lipoprotein metabolism. apo A II activates hepatic lipase(HL) apo A I activates LCAT apo C II activates lipoprotein lipase (LPL) c. To recognize the lipoprotein receptors. § 5.6 Metabolism of plasma lipoprotein 1. CM • Chylomicrons are formed in the intestinal mucosal cells and secreted into the lacteals of lymphatic system. structure of CM Apolipoproteins phospholipids Cholesterol Triacylglycerols and cholesteryl esters Metabolic fate of CM summary of CM • Site of formation: intestinal mucosal cells • Function: transport exogenous TG • key E: LPL in blood HL in liver • apoCⅡ is the activator of LPL • apo E and apo B-48 will be recognized by the LRP receptor 2. VLDL • Very low density lipoproteins (VLDL) are synthesized in the liver and produce a turbidity in plasma. Nascent VLDL Metabolic fate of VLDL and production of LDL Summary of VLDL • Formation site: liver • Function: VLDL carries endogenous triglycerides from liver to peripheral tissues for energy needs. • key E: LPL in blood HL in liver 3. LDL • Most of the LDL particles are derived from VLDL, but a small part is directly released from liver. They are cholesterol rich lipoprotein molecules containing only apo B-100. LDL receptors Cholesterol ester protein Cholesterol LDL Cholesteryl oleate Amino acids LDL binding Internalization Lysosomal hydrolysis Michael Brown and Joseph Goldstein were awarded Nobel prize in 1985 for their work on LDL receptors. Summary of LDL • Formation site: from VLDL in blood • Function: transport cholesterol from liver to the peripheral tissues. LDL concentration in blood has positive correlation with incidence of cardiovascular diseases. Fates of cholesterol in the cells 1. Incorporated into cell membranes. 2. Metabolized to steroid hormones. 3. Re-esterified and stored. The reesterification is catalyzed by ACAT. 4. Expulsion of cholesterol from the cell, esterified by LCAT and transported by HDL and finally excreted through liver. 4. HDL • LDL variety is called “ bad cholesterol” whereas HDL is known as “ good cholesterol” . Liver Heart VLDL “Good” Excretion “BAD” LDL Cholesterol Deposit HDL Forward and reverse cholesterol transport Reverse cholesterol transport • Cholesterol from tissues reach liver, and is later excreted. This is called reverse cholesterol transport by HDL. Metabolism of HDL in reverse cholesterol transport CETP • Cholesterol ester transfer protein (CETP) transfer cholesterol ester in HDL to VLDL and LDL. Summary of HDL • Formation site: liver and intestine • Function: transport cholesterol from peripheral tissues to liver summary of lipoprotein metabolism § 5.7 Hyperlipidemias classification Lipoprotein Blood lipids Ⅰ CM TAG↑ ↑ ↑ CH↑ Ⅱa LDL CH↑ ↑ Ⅱb LDL, VLDL CH↑ ↑ TAG↑ ↑ Ⅲ IDL CH↑ ↑ TAG↑ ↑ Ⅳ VLDL Ⅴ VLDL, CM TAG↑ ↑ TAG↑ ↑ ↑ CH↑