STRUCTURE AND METABOLISM Of LIPIDS AND LIPOPROTEINS. R. Mohammadi Biochemist (Ph.D.) Faculty member of Medical Faculty

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1 STRUCTURE AND METABOLISM Of LIPIDS AND LIPOPROTEINS R. Mohammadi Biochemist (Ph.D.) Faculty member of Medical Faculty

2 STRUCTURE OF LIPIDS AND LIPOPROTEINS

3 DEFINTITION: Compounds Insoluble in water But Soluble in Organic Solvents such as Ether, Benzene, Chloroform, etc

4 CLASSIFICATION ACCORDING TO THEIR STRUCTURES SIMPLE LIPIDS Triacylglycerols (Fats) Waxes Complex Lipids Phospholipids Glycolipids STEROIDS POLYISOPRENOIDES

5 CLASSIFICATION ACCORDING TO THEIR FUNCTIONS STORAGE LIPIDS Triacylglycerols (Fats) Waxes MEMBRANE LIPIDS Phospholipids Glycolipids Cholesterol HORMONES Steroids Eicosanoides VITAMINES Vit A Vit E Vit K Vit D OTHERS Surfactant Bile Acids Dolichol Ubiquinone (Coenzyme Q) Phosphatidylinositol 4,5- bisphosphate

6 FATTY ACID

7 CLASSIFICATION OF FATTY ACIDS According to Number of Carbons: SHORT CHAIN (2 to 4 carbons) MEDIUM CHAIN (6 to 10 carbons) LONG CHAIN (12 to 26 carbons)

8 CLASSIFICATION OF FATTY ACIDS According to Presence of Double Bonds: SATURATED FATTY ACIDS (SFAs) Lauric acid (12C) Myristic acid (14C) Palmitic Acid (16C) Stearic Acid (18C) Arachidic Acid (20C) Behenic Acid (22C) Lignoceric Acid (24C)

9 UNSATURATED FATTY ACIDS (USFAs) Monounsaturated Palmitoleic acid (16:1;9 ) w7 Oleic acid (18:1;9) w9 Polyunsaturated Linoleic acid (18:2;9,12 ) w6 Linolenic acid (18:3;9,12,15) w3 Arachidonic acid (20:4;5,8,11,14) w6

10 DOUBLE BONDS Can be: Conjugated Unconjugated (-CH=CH-CH=CH-) or (-CH=CH-CH2-CH=CH-) Cis or Trans

13 trans FATTY ACIDS Lead to higher incidence of cardiovascular disease, because of 1) Increasing LDL 2) Decreasing HDL 3) Increasing TAG 4) Increasing inflammatory response

14 TRIACYLGLYCEROL

16 MEMRANE LIPIDS

19 CHOLESTEROL Free Cholesterol Cholesteryl Ester

21 EICOSANOIDES CYCLOOXYGENASE Prostaglandines (PGs) PGE, PGF, PGI Thromboxanes (TXs) TXA LIPOOXYGENASE Leukotrienes LTA, LTC, LTD, LTE

22 20:3;8,11,14 (w6) Series 1 20:4;5,8,11,14 (w6) Series 2 20:5;5,8,11,14,17 (w3) Series 3

23 TXA3 < TXA2 PGI3 = PGI2

25 LIPOPROTEIN METABOLISM

27 MAIN LIPOPROTEINS CHYLOMICRON VERY LOW DENSITY LIPOPROTEINS (VLDL) LOW DENSITY LIPOPROTEINS (LDL) HIGH DENSITY LIPOPROTEINS (HDL)

29 MAJOR LIPOPROTEINS LIPOPROTEINS DENSITY (g/ml) DIAMETER (nm) ELECTROPHO RESIS PROTEIN (%) TRIGLYCE RIDE (%) CHOLESTER OL (%) PHOSPHOLI PID (%) Chylomicron < Origin VLDL o Pre-b LDL b HDL a

30 APOLIPOPROTEINS Apo A-I, A-II, A-IV Apo B-100, Apo B-48 Apo C-I, C-II, C-III Apo D Apo E1, E2, E3, E4

31 APOLIPOPROTEINS FUNCTIONS As Structural Components eg, Apo B-100, Apo B-48 As Enzyme Activators eg, Apo C-II, Apo A-I As Enzyme Inhibitors eg, Apo C-III, Apo A-II As Ligands eg, Apo B-100, Apo E

33 Enzymes Involve in Metabolism of Lipoproteins Lipoprotein Lipase (LPL) Hepatic Lipase (HL) Lecithine: Cholesterol Acyltransferase (LCAT)

34 Transfer Proteins Involve in Metabolism of Lipoproteins ATP Binding Cassette Transporter-1 (ABC-1) Cholesteryl Ester Transport Protein (CETP) Phospholipid Transport Protein (PLTP) Apo D

35 Receptors Involve in Metabolism of Lipoproteins B/E Receptor LDL Receptor Related Protein (LRP) VLDL Receptor Scavenger Receptor Class A (SR-A) Scavenger Receptor Class B Type 1 (SR-B1)

36 REVIEW OF LIPOPROTEIN METABOLISM

37 CHYLOMICRON TRANSPORTS DIET LIPIDS FROM INTESTINE FC, PL B48 A NASCENT CM C E B48 C MATURE CM A E LPL (C-II, PL) FFA, Glycerol C A B48 REMNANT CM E INTESTINE TISSUES eg, Fatty tissue & Muscle LIVER

38 VLDL TRANSPORTS LIVER LIPIDS FC, PL B100 NASCENT VLDL C E B100 C MATURE VLDL E LPL (C-II, PL) FFA, Glycerol C B100 IDL E TISSUES eg, Fatty tissue & Muscle LIVER

39 LDL IS CATABOLITE OF VLDL SPECIFIC UPTAKE B100 IDL FC B100 LDL CE SCAVENGER SYSTEM

41 HMG-CoA Reductase Receptor ACAT (Acyl-CoA Cholesterol acyltransferase)

42 HMG-CoA REDUCTASE IS REGULATORY ENZYME

43 HDL PARTICIPATE IN REVERSE CHOLESTEROL TRANSFER C A-I CE E A-I A-II A-I A-II HDL3 E HDL2 E LCAT FC C E LCAT C HDL CYCLE LCAT C HEPATIC LIPASE FFA, PL, CE A

44 DYSLIPIDEMIAS Hyperlipoproteinemia Hyperlipidemia Hypolipoproteinemia

45 HYPERLIPIDEMIA PRIMARY TYPE I TYPE II TYPE III TYPE IV TYPE V SECONDARY DIABETICS Thyroid Dysfunction OCP (Oral Contraceptive)

46 CLINICAL PRESENTATION ATHEROSCLEROSIS PANCREATITIS HEPATOSPLENOMEGALY XANTHOMA

MTABOLIC SYNDROME The insulin resistance associated with obesity

hypertension, and several types of cancers.

the patient becomes diabetic, so the condition between the onset

47 MTABOLIC SYNDROME The insulin resistance associated with obesity increases the risk of developing type 2 diabetes, heart disease, hypertension, and several types of cancers. Increased risk of some of these diseases may occur long before the patient becomes diabetic, so the condition between the onset of insulin resistance and development of type 2 diabetes is referred as metabolic syndrome

48 METABOLIC SYNDROME WHO Defines Metabolic Syndrome as Two or More of the Following Conditions: Abdominal obesity Dyslipidemia (Increased VLDL and Decreased HDL) Hypertenstion Insulin Resistant (Modest increase in FBS)

49 TNFa INCDUCES DYSLIPIDEMIA TNFa Lipoprtein Lipase Hormone-sensitve Lipase Clearance of VLDL from Circulation Hepatic Synthesis of TAGs Release of FFAs Into Circulation Blood VLDL Hepatic Synthesis of VLDL Hepatic Uptake of FFAs

50 TNFa INDUCES DYSLIPIDEMIA TNFa Expression & Activity of LCAT Expression of ABC Transporters Expression of APo A-I & Apo-A-IV Blood HDL

51 FFAs INDUCE HYPERGLYCEMIA FFAs Activation of PKC Competitive Inhibition of GLUT2 & GLUT4 Phosphorylation of IRS-1 & IRS-2 Interfering with GLUT4 Translocation In Muscle Down-Regulation of Gluconeogenesis In Liver Blood Glucose

52 PANCREATIC COMPENSATION Hyperinsulinemia Increased Cell Proliferation Stimulation of Sympatthetic Nervous System Normal or Near Normal Blood Glucose Increased Risk of Different Types Of Cancers Na & Water Retention Vasoconstriction Hypertension

53 DECOMPENSATION PROCESS Increased FFAs and/or Cytokines Gradual Loss of the Ability of the Pancreas to Overproduce Insulin Increased Blood Glucose Type 2 Diabetes Begins

54 High Triglyceride with Normal Cholesterol Familial Hypertriglyceridemia Familial Hyperchylomicronemia Hyperlipoproteinemia Type V Apo C-II Deficiency Apo C-III excess Diabetes/insuline resistance Chronic renal failure and nephrotic syndrome Esterogens, Corticosteroides, Beta-blockers Obesity High carbohydrate diets Physical inactivity Cigarette smoking Excess alcohol intake

55 Familial Hyperchylomicronemia (Type I) Is Rare (1 in ) LPL Deficiency Chylomicron Exogenous Hypertriglyceridemia Very High TG Lipemic Serum with Creamy Layer Thick Band at Origin Pancreatitis

56 Familial Hypertriglyceridemia (Type IV) Is Common (1 in 500) Apo B-100 synthesis is normal, but production of VLDL is high Familial Hypertriglyceridemia Endogenous Hypertriglyceridemia Increased VLDL High TG Thick pre-b Band Triad of Obesity, Hyperinsulinemia, Hyperglycemia,

57 HYPERLIPOPROTEINEMIA TYPE V Increased Chylomicron & VLDL Thick Origin & pre-b Bands

High Cholesterol with High LDL-C Polygenic

Hypothroidism Nephrotic syndrome Chronic

58 High Cholesterol with High LDL-C Polygenic (Nonfamilial) Hypercholestrolemia Familial Hypercholestrolemia Familial defective ApoB Hyperapobetalipoproteinemia Sitosterolemia Hypothroidism Nephrotic syndrome Chronic obstructive liver disease Obesity Excess Dietary cholesterol and/or saturated fat

59 Familial Hypercholeterolemia Results from mutation in LDL (B/E) receptor gene Homozygous occurs 1 in Heterozygous occures 1 in 500

60 Apo B100 Deficiency Results from mutation apo B-100 gene Estimated frequency is 1 in 750

61 Hyperapobetalipoproteinemia Is characterized by apo B-100 concentration May be due to increase synthesis of VLDL or apo B-100, which leads to formation of atherogenic small dense LDL LDL-C is normal or moderately increased The ratio of LDL cholesterol to apo B-100 is reduced

62 High Triglyceride with High Cholesterol Familial Combined Hypelipidemia (Type 2B) Familial Dysbetalipoproteinemia (Type 3) Severe hypothyroidism Diabetes/insuline resistance Nephrotic syndrome High-dose steroides Obesity

63 Familial Combined Hyperlipidemia Is a relative common disorder May be seen as simple hypercholestrolmiaresults (Type IIa) simple Hypertriglyceridemia (Type IV) Mixed (Type IIb) Estimated frequency is 1 in 100 Appears to be multifactorial

type III phenotype is only 1 in 10000 Increase in Remnants

64 Dysbetalipoprotenemia (Type III) Patients are E2/E2 This geotype is relativel commom (1 in 100), but expression of type III phenotype is only 1 in Increase in Remnants Presense of beta-vldl with high cholesterol/triglyceride ratio

65 Isolated Low HDL-C Familial Hypobetalipoproteinemia Apo A-I deficiency and Apo C-III deficiency Apo A-I variants Tangier Disease LCAT deficiency Anabolic steroides, beta-blockers Physical inactivity Obesity High-carbohydrate, low-fat diets

66 Familial Hypoalphalipoproeinmia Decrese synthesis or increase catabolism of HDL or Apo A-I Low HDL (<30 mg/dl in men and >40 mg/dl in women)

67 Aalphalipoproteinemia (Tangier Disease) Is a rare disorder Results from mutations in ABCA1 gene In hemozygous, there in no HDL and Total Cholesterol is low There is reduced LDL and abnormal remnants

68 Isolated High HDL-C CETP defects Esterogens Alcohol intake

69 Isolated Low Total Cholesterol Abetalipoproteinemia Hypobetalipoproteinemia Chylomicron retention disease

ATP III (Adult Treatment Panel III) CLASSIFICATION C IN ADULTS

ATP III (Adult Treatment Panel III) CLASSIFICATION C IN ADULTS LABORATORY AND RISK FACTORS OF ATHEROSCLEROSIS S R. Mohammadi Biochemist (Ph.D.) Faculty member of Medical Faculty RISK FACTORS FOR CHD Clinical Risk Factors Laboratory Risk Factors MAJOR CLINICAL RISK