LDL & HDL METABOLISM

LDL & HDL METABOLISM

1. LDL & HDL Metabolism Gandham.Rajeev Email:[email protected]

2. LDL Metabolism LDL is bad-cholesterol. It transports cholesterol from liver to peripheral tissues. LDL contains only one lipoprotein Apo B-100. LDL particles are derived from VLDL. Small part is directly released from liver. Half-life is 2 days.

3. Structure of LDL

4. Metabolism LDL is taken up by peripheral tissues by receptor-mediated endocytosis. LDL receptors are present in all tissues. But most abundant in hepatic cells. LDL receptors located in specialized regions called clathrin -coated pits. Binding of LDL to receptor is by apo-B-100. It is highly regulated.

5. LDL Receptors It is a polypeptide, consists of 839 amino acids. Contains extracellular & intracellular domains. Extracellular domain is responsible for binding of apo-B-100 & apo -E. Intracellular domain is responsible for the clustering of LDL receptors into regions of plasma membrane termed coated pits.

6. Apo-B-100 binds to apo-B-100 receptor, receptor LDL complex is internalized by endocytosis. The endosome vesicles fuses with lysosomes. The receptor is recycles & returned to the cell surface.

7. LDL particles, apoproteins & cholesterol esters are hydrolyzed by hydrolases, forming free amino acids & free cholesterol. 70% of LDL is degraded in the liver & remaining is in extra-hepatic tissues. Free cholesterol incorporated into plasma membrane or stored in cells.

8. Uptake & fate of LDL

9. Functions of LDL 75% of plasma cholesterol is incorporated into LDL particles. LDL transports cholesterol from liver to peripheral tissues. The transported cholesterol has following fates: For synthesis of steroids. May be incorporated into membranes. May be esterified to MUFA & stored.

10. Forward & reverse transport of cholesterol

11. LDL & its clinical significance LDL concentration is increased in cardiovascular diseases. Small fraction of cholesterol is taken up by macrophages. Increased levels of LDL or modified LDL or oxidized LDL increases the fraction of cholesterol taken by macrophages.

12. There is an LDL infiltration through arterial walls & taken up by macrophages or scavenger cells. This is starting event of atherosclerosis, leading to MI . These cells become engorged with cholesterol, foam cells are formed.

13. These are deposited in sub-endothelial space triggering the formation of atheromatous plaque. Leads to thrombosis & coronary artery disease. LDL is a bad-cholesterol. Defects in LDL receptor synthesis leads to familial hypercholesterolemia.

14. Lipoprotein (A) Lp (a) is associated with myocardial infarction & is called as “little rascal” Lp (a) is attached to apo-B-100 by a disulfide bond. In 40% population, there is no detectable level of Lp (a) in serum. Lp (a) levels >30 mg/dl is susceptible for heart attack at a younger age.

15. Indians have higher levels of Lp (a) than western populations. Lp (a) interferes with plasminogen activation & impairs fibrinolysis. Leads to unopposed intravascular thrombosis & possible myocardial infarction.

16. HDL Metabolism HDL is a good cholesterol. Transports cholesterol from peripheral tissues to liver. Synthesized in liver. Major apoproteins in HDL are Apo A1, with some Apo A2, Apo C & Apo E. HDL is an plasma reservoir of Apo C & Apo E, which can be transferred to VLDL & chylomicrons .

17. Metabolism Intestinal cells synthesize components of HDL & release into blood. Nascent HDL are discoid in shape. Free cholesterol is taken up by the HDL Apo A-1 of HDL activates LCAT. LCAT binds to HDL disc . Cholesterol from cell is transferred to HDL by cholesterol efflux regular protein, which is an ABC protein.

18. Lecithin is a component of lipid bilayer of HDL disc. Second carbon of lecithin contains PUFA. This PUFA is transferred to 3 rd OH group of cholesterol to form cholesterol esters. Cholesterol esters moves into the interior of HDL disc. HDL becomes spherical shape with lot of cholesterol esters are formed. This is called as HDL-3.

19. Mature HDLs are taken up by liver cells by apo A-1 mediated receptor mechanism. HDL is taken up by hepatic scavenger receptor B1. Hepatic lipase hydrolyzes HDL phospholipids & TAG, cholesterol esters are released into liver cells. These cholesterol esters are used for the synthesis of bile acids or excreted as bile.

20. When HDL3 remains in circulation, cholesterol esters from HDL is transferred to VLDL, IDL & LDL by a cholesterol ester transfer protein (CETP). TAG from VLDL,IDL & LDL is transferred to HDL in exchange for cholesterol esters.

21. HDL particles rich in TAG & spherical are called as HDl-2 These particles are first acted upon by hepatic triglyceride lipase (HTGL) Efflux of cholesterol from peripheral cells to HDL is mediated by ABC transporter protein.

22. HDL Metabolism

23. Functions of HDL HDL is the transports cholesterol from peripheral tissues to liver, called as reverse cholesterol transport. Cholesterol is excreted through bile. Cholesterol excretion needs prior esterification with PUFA. PUFA reduces serum cholesterol levels. PUFA is anti- atherogenic .

24. HDL & its clinical significance Serum HDL levels are inversely related to the incidence of MI. HDL is “anti- atherogenic ” or protective in nature. It is a good cholesterol. HDL levels <35mg/dl increases risk, >65mg/dl reduces the risk of CAD.

25. Free fatty acids Complexed with albumin in plasma. FFA is derived from lipolysis of TAG stored in adipose tissue by hormone sensitive lipase. FFA may be long chain saturated or unsaturated FA. & are transported to heart, skeletal muscle, liver & other tissues. FFA are either oxidized or incorporated into tissue lipids.

26. In tissue cells, FFA-albumin complex is dissociated, FFA binds with fatty acid transport protein. It is a co-transport with sodium. Half-life of FFA is 1-2 minutes. During starvation, 40-50% of energy is met by oxidation of FFA.

27. References Textbook of Biochemistry-U Satyanarayana Textbook of Biochemistry-DM Vasudevan

28. Thank You