Lipoproteins II 19-2-2021.pptx good luck.

Lipoprotina

1. Lipoprotein metabolism; role in plasma cholesterol homeostasis; and clinical disorders Prof Kunzang Chosdol Department of Biochemistry

2. HDL metabolism overview Feingold and Grunfeld , 2018 cholesterol ester transfer protein (CETP) ABCA 1, ATP-binding cassette transporter A1 ; LCAT , lecithin:cholesterol acyltransferase; SR-B1 , scavenger receptor B1;

3. HDL metabolism : mechanisms for atheroprotection Elicits cholesterol efflux and mediates reverse cholesterol transport

4. HDL metabolism HDL concentrations increase reciprocally with plasma triacylglycerol concentrations directly with the activity of lipoprotein lipase May be due to surplus phospholipid and apo A-I (released during hydrolysis of chylomicrons and VLDL), contributing toward the formation of preβ-HDL and discoidal HDL HDL2 concentrations are inversely related to the incidence of atherosclerosis (reflect the efficiency of reverse cholesterol transport)

5. Lipoprotein lipase (LPL): Lipoprotein lipase is an enzyme that degrades circulating triglycerides embedded in VLDL and in chylomicrons that travel through the bloodstream LPL is located on the walls of blood capillaries, anchored to the endothelium by negatively charged proteoglycan chains of heparan sulfate Found in heart, adipose tissue, spleen, lung, renal medulla, aorta, diaphragm, and lactating mammary gland , not active in adult liver Lipoprotein lipase requires apolipoprotein -CII as cofactor , which is carried by a chylomicron , VLDL and IDL, for activation

6. Hepatic lipase (HL) Hepatic lipase (HL) is a key enzyme catalyzing the hydrolysis of triglycerides (TG) and phospholipids (PLs) in several lipoproteins One of the principal functions of hepatic lipase is to convert IDL to LDL HL is involved in the remodelling of remnant, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and the production of small, dense low-density lipoproteins ( sd -LDLs) Over 220 mutations of LPL is known - Impairs utilization of triglycerides from TG rich lipoproteins (CM, VLDL) Clinical features : type one familial dyslipidemias or hyperchylomicronemia with recurrent pancreatitis, enlarged liver and xanthomas

7. LDL receptor family ( Asn , Pro, any aa , Tyr)  scavenger receptors

8. LDL receptor Brown and Goldstein: Nobel Prize, 1985 Multiple domains : LDL binding, interactions for release of LDL in endosome(acidic); clathrin interaction and endocytosis Extracellular amino-terminal region Bind to Apo B-100 Endocytosed: fusion with endosome; release of LDL; hydrolysis (cholesterol ester and Apo B) Recycling: of receptor to plasma membrane (10 minutes) LDL receptor

9. Function of LDL receptor Endocytosis of LDL and other LP Release free cholesterol into liver Incorporate into plasma membrane Inhibit new LDL receptors Inhibit cholesterol synthesis Promote ACAT activity (FC -> CE) • Regulated by SREBP monitors free cholesterol

10. Hegele et al, Nature Reviews Genetics, 2009. OVERVIEW OF LIPOPROTEIN METABOLISM The metabolism of (1) TG (2) LDL-cholesterol and (3) HDL-cholesterol Acyl CoA:diacylglycerol acyltransferase adipose TG lipase hormone sensitive lipase LDLR-related protein-1 Niemann -Pick C1-like 1 LDL is endocytosed by peripheral cells and hepatocytes by LDLR/adaptor protein (AP). cholesterol ester transfer protein (CETP) endothelial lipase (LIPG), Proprotein convertase subtilisin / kexin type 9 Dietry TG

11. Lipoprotein metabolism and disease Hyperlipidemias: Primary: monogenic ; polygenic Secondary: diabetes mellitus, hypothyroidism, Cushing’s syndrome ; diet Hypolipidemias : Hypobetalipoproteinemia Abeta-lipoproteinemia Loss of Proprotein convertase subtilisin / kexin type 9 (PCSK9) Loss of Intestinal Niemann-Pick C1-Like transport protein

12. GPIHBP1 - a capillary endothelial cell protein that provides a platform for LPL-mediated processing of chylomicrons Activator of  lipoprotein lipase Uptake of lipoproteins through LDLR family ApoCIII inhibits  lipoprotein lipase & hepatic lipase Glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1

13. Single gene mutations responsible for primary hyperlipoproteinemias Hypertriglyceridemia Defect Lipoprotein elevated LPL deficiency LPL Chylomicrons, VLDL Familial apoC -II deficiency ApoC -II Chylomicrons, VLDL ApoA-V deficiency ApoA-V Chylomicrons, VLDL Familial dysbetalipoproteinemia ApoE (ApoE2) Chylomicron and VLDL remnants Combined Hyperlipidemia Familial hepatic lipase Hepatic Lipase VLDL remnants, HDL Hypercholesterolemia Familial hypercholesterolemia (FH) LDL-Receptor LDL Defective ApoB-100 ApoB-100 LDL Autosomal Dominant hypercholesterolemia PCSK9 LDL Autosomal Recessive hypercholesterolemia LDL adaptor protein LDL Proprotein convertase subtilisin / kexin type 9

14. Secondary hyperlipidemias: some examples Condition Serum lipid pattern Diabetes mellitus Increased triglycerides, decreased HDL Obesity Increased triglycerides, decreased HDL Hypothyroidism (Regulate LDL-R, LPL, CETP expression) Increased LDL, increased total cholesterol, increased triglycerides (in some cases) Chronic kidney disease (Insulin resistance) Increased LDL, decreased HDL, increased triglycerides Alcohol excess Increased triglycerides, increased HDL Cholestasis Increased LDL, increased total cholesterol

15. Reference plasma cholesterol levels LDL: <100 : Optimal 100-129 : Near optimal / above optimal 130-159 : Borderline high 160-189 : High 190 : Very high TOTAL cholesterol < 200 - Desirable 200-239 Borderline high 240 High HDL >40 Normal < 40 LOW ≥60 HIGH TRIGLYCERIDES <150 Normal 150-199 Borderline high 200-499 High 500 Very high (mg/dl) (mg/dl) (mg/dl) (mg/dl)

16. Management Principles NONPHARMACOLOGIC INTERVENTIONS: diet and lifestyle PHARMACOLOGIC MANAGEMENT : Fibrates (activate PPAR-peroxisome proliferator activated receptor-decrease production of VLDL and removal from blood) HMG-CoA Reductase inhibitors (statin) Cholesterol absorption inhibitors (Ezetimibe) Bile acid sequestrant ( Cholestyramine )

17.   Atherosclerosis - Is a chronic multistep and multifactorial disease in which plaques made up of fat, cholesterol, calcium and other substances, build up in artery walls

18. Pathogenesis of Atherosclerosis :

19. Assessment of atherosclerotic cardiovascular disease (ASCVD): Clinical evidence of ASCVD. Other conditions known to be associated with high or very high risk for ASCVD (e.g. ≥ 3 major ASCVD risk factors , diabetes mellitus, chronic kidney disease stage 3B or 4, LDL-C levels ≥ 190 mg/ dL ) Major risk factors for ASCVD include: Age ≥ 45 years in men and ≥ 55 years in women Family history of atherosclerotic coronary heart disease in a first-degree man relative < 55 years of age, or a first-degree woman relative < 65 years of age Current cigarette smoking High blood pressure (e.g., ≥ 140 mg Hg systolic or ≥ 90 mm Hg diastolic, or treated with high blood pressure medications High high density lipoprotein cholesterol levels (e.g., < 40  mg/ dL )

20. Lipoprotein metabolism and disease Hyperlipidemias: Primary: monogenic ; polygenic Secondary: diabetes mellitus, hypothyroidism, Cushing’s syndrome ; diet Hypolipidemias : Hypo- betalipoproteinemia Abeta-lipoproteinemia Loss of function of Proprotein convertase subtilisin / kexin type 9 (PCSK9) and Intestinal Niemann-Pick C1-Like (NPC1L1)transport protein

21. Familial Hypobetalipoproteinemia ( FHBL ) and Abetalipoproteinemia (ABL) Rare diseases characterized by hypocholesterolemia and malabsorption of lipid-soluble vitamins Leading to retinal degeneration, neuropathy, and coagulopathy , Hepatic steatosis is also common There is improper packaging and secretion of apolipoprotein B-containing lipoproteins Several mutations in the apoB , PCSK9 and MTP genes  Mutations in the ANGPTL3 (Angiopoietin-like protein 3) gene cause familial combined hypolipidemia , it is an inhibitor of LPL and HL

22. Loss of function mutations in PCSK-9 cause FHBL Appears to lower risk for CAD and have no adverse sequelae Phase III clinical trials are underway examining the effect of PCSK-9 inhibitors on cardiovascular events in combination with statin drugs

23. Tangier disease  Also known as  Familial alpha-lipoprotein deficiency or hypo-alpha- lipoproteinemia   It is a rare inherited disorder ( autosomal recessive ) characterized by a severe reduction in the amount of HDL Mutations to chromosome 9q31 lead to a defective ABCA1 transporter Inability to transport cholesterol out of cells - deficiency of HDL -which is a risk factor for coronary artery disease The treatment modality is diet modification

24. Separation of lipoproteins:

25. Effect of Exercise Increases LPL activity in muscle Reduces TGL from the particle Reduction in weight Increases HDL Effect of diet Vegetarian diet – Cholesterol intake less Reduced Carbohydrate – VLDL - TG Reduced Fat – Reduces CM-TG Unsaturated fats ( Mono and Poly)- Reduction in Plasma cholesterol Fiber – decreases cholesterol absorption

26. Postprandial Changes in Plasma Lipid Metabolism Fat storage via LPL Exchange of cholesterol for VLDL TG in HDL (CETP) LCAT activity = esterification of free cholesterol (HDL) These postprandial changes are beneficial in maintaining whole body homeostasis of glycerides and cholesterol

27. Questions (CM) What are the lipids carried by CM? Where is CM formed? How does the CM release FFA? What is the fate of the FFA and Glycerol? Where is the LPL found? What are the components of Remnant CM? QUESTIONS ( VLDL ) Where is VLDL formed? What are the lipids Carried by VLDL ? Which lipid is delivered by VLDL ? What is the mechanism of FFA release from VLDL ? What is the fate of Remnant VLDL ? What are the lipids present in excess when VLDL becomes VLDLR ? Questions ( LDL ) How is LDL formed? What is IDL ? How is CE transferred from HDL to IDL ? What is CETP ? The clinical importance of small dense LDL ? oxidized LDL? Lipoprotein (a)? Questions

28. Thank You