Metabolism of lipoproteins & its disorders(Chylomicron & VLDL & LDL).pptx

For Medical, Paramedicals and Allied Health sciences students

1. Transportation of Lipids / Metabolism of lipoproteins

2. Exogenous pathway eg: Metabolism of Chylomicrons & Endogenous pathways - Metabolism of VLDL, LDL& - reverse cholesterol transportation: HDL

3. Chylomicrons Density (g/ mL ) Protein % CH % TG % PL % Apo proteins Site of syn Functions < 0.95 2 4 85 9 Apo-A, B48, C & E Intestine Transport of dietary TGs and cholesterol esters from intestine to peripheral tissues and liver.

4. Chylomicron metabolism Carry dietary TG, Ch & chE to the peripheral tissues. C-II & PL + A-II & C-III - -E Thoracic duct Some of the PL LDL receptor protein (LPL)

5. Endogenous pathways Very low density lipoproteins ( VLDL ) / IDL Density (g/ mL ) Protein % CH % TG % PL % Apo proteins Site of syn Functions 0.95 – 1.006 10 15 55 20 Apo-B100, C &E Liver Transports endogenous TGs from liver to peripheral tissues.

6. Transport endogenous Triglycerides , Cholesterol from liver to the peripheral tissues. Half life is 1 -3hrs Cholesterol Ester Transfer Protein - CETP Transfer of CE and TG b/w HDL & VLDL & LDL TG

7. Low Density lipoprotein (LDL) Density (g/ mL ) Protein % CH % CE % TG % PL % Apo proteins Site of syn Functions 1.006-1.063 20 10 40 8 22 Apo-B100 Plasma VLDL Transports cholesterol from liver to peripheral tissues. 50%

8. -E CE TG TG 30% 70% Half life is 2 days

9. Tissue uptake of LDL LDL loaded with Cholesterol is taken up by peripheral tissues by LDL receptors mediated endocytosis Scavenger receptors (macrophages derived from monocytes) mechanisms Clathrin Maintain their cell membrane (All tissues) Steroid hormone synthesis (adrenal cortex) Bile acids synthesis (hepatocytes)

10. Transport Cholesterol from liver to the peripheral tissues. Receptors mediated endocytosis

11. Scavenger receptors / Receptor independent mechanism Phagocytic macrophages (monocytes ) It recognize LDL that has been modified – oxidized LDL Uptake of oxidized LDL by macrophages in the arterial wall is potentially dangerous Macrophages overloaded with CE are called foam cells

12. Lipoprotein(a) not apoprotein -A Lp (a) is a LDLvariant containing a protein- apolipoprotein (a). It is attached to apo-B100 of LDL by a disulfide bond It is highly atherogenic & impairs fibrinolysis It is an important marker of CHD

13. Endogenous pathway Metabolism of High-Density Lipoproteins (HDL ) / Reverse cholesterol transport

14. Density (g/ mL ) P % C % CE % TG % PL % Apo proteins Site of syn Functions 1.063-1.210 40 2 23 5 30 Apo-A, C-II & E Liver & Intestine Transports cholesterol from peripheral tissues to liver. Serves as a circulating reservoir of Apo C-II & E Transfers cholesteryl esters to VLDL & LDL in exchange for TG & PL from these particles High-Density Lipoprotein (HDL) 25%

15. Enzymes and Transfer Proteins Functions Lecithin - Cholesterol Acyl transferase - LCAT Esterifies the cholesterol (Cholesterol→ Cholesterol ester) content of HDL to prevent it from reentering the cells Acyl-CoA: Cholesterol Acyl transferase- ACAT Formation of cholesterol esters in cells ATP-Binding Cassette-1- ABC-1 Transfer of free CH from plasma membrane to ApoA-1 (HDL) Cholesterol Ester Transfer Protein - CETP Transfer of CE and TG b/w HDL & VLDL & LDL Phospholipids Transfer Protein - PLTP Transfers phospholipids b/w lipoproteins Scavenger receptor class-B type-1- SR-B1 Multi ligand receptor that binds not only HDL but VLDL & LDL also

16. LCAT : Lecithin-Cholesterol Acyl transferase ABC-1 : ATP-binding cassette-1 SR-B1: scavenger receptor class B type-1 CETP: Cholesterol Ester Transfer Protein ABC-1 Hepatic HDL receptor +

17. Significance of reverse cholesterol transport Cellular & lipoprotein cholesterol is delivered back to the liver It prevents deposition of cholesterol in the tissues anti- atherogenic property of HDL to protect LDL from oxidation due to the association of esterase enzyme paraoxanase with HDL Paraoxanase may destroy oxidized LDL HDL decreases the risk of coronary heart diseases

18. Disorders of lipoproteins ( Lipoproteinemias/ Hyperlipidemias ) ( Frederick son classification of lipoproteinemias )

19. It causes complex & different disease mechanism, it classified into Primary hyper- lipoproteinemia : is completely genetic disorders. Secondary hyper- lipoproteinemia : is manifested due to other disorders (Nephrotic syndrome, type-II DM & cirrhosis of liver ) . Coronary & cerebral vessels are more commonly affected Deposition of lipid in subcutaneous tissue leads to xanthomas HYPER LIPOPROTEINEMIAS (Increased lipoproteins in the blood)

20. Lipoproteinemias Metabolic Defect Elevated -Lp CH TG Clinical feature Type-I: Familial lipoprotein lipase deficiency Lipoprotein lipase & Apo C-II deficiency chylomicrons N ↑↑ Eruptive xanthoma , hepatomegaly & Abdominal pain Type –IIA: Familiar Hypercholesterolemia LDL receptor defect. Apo-B ↑se LDL ↑↑ N Atherosclerosis, CDA & Xanthelesma Type –IIB: Familiar Hypercholesterolemia Overproduction of Apo-B LDL & VLDL ↑↑ ↑ Corneal arcus Type-I, IV & V: Hyper triglyceridemia, Type- IIa : Hyper cholesterolemia, Type- IIb & III: combined Hyperlipidemia

21. Lipoproteinemias Metabolic Defect Elevated -Lp CH TG Clinical feature Type – III: broad beta disease Apo-E & Apo-CII broad beta –VLDL(LDL & IDL) ↑↑ ↑ Palmar xanthomas , atherosclerosis Type-IV: Familiar Hyper triaglycerolemia Overproduction of VLDL& Apo –C-II ↑ sed VLDL ↑ ↑↑ Associated with diabetes, heart disease, obesity Type-V : Combined hyper lipidaemias / hyper triglyceridemia Secondary to other causes ↑ sed VLDL & chylomicrons N ↑↑ Ischemic heart diseases & chronic pancreatitis Type-I, IV & V: Hyper triglyceridemia, Type- IIa : Hyper cholesterolemia, Type- IIb & III: combined Hyperlipidemia

22. Palmar xanthomas (Effects the palms) Corneal arcus ( D eposition of lipid in the peripheral cornea ) Eruptive xanthoma , (small yellow nodules associated with deposition of TG . lesions and bumps that appear on the skin) Xanthelasma (yellow plaques deposits under the periorbital skin / near canthus of eyelid) Tuberous Xanthomas (deposition of yellow plaqes with TG& chol in tendons or elbows &knees) Acanthocytosis Irregular shaped RBCs with spikes on the outside

23. Lipoproteinemias Metabolic Defect Decreased -Lp CH TG Clinical feature Abeta-lipoproteinemia Apo-48 ↓ & Apo B-100 ↓↓ sed LDL is completely absent (TG is not incorporated into VLDL & Chylomicrons) ↓↓ ↓ Malabsorption : causes mental & physical retardation. Acanthocytes Familial α- lipo protein deficiency ( Tangier’s disease) - Mutation in the ABC-1 protein HDL ↓↓↓ & A–I ↓ N N “ CE” are accumulated in tissues leads to Increased risk of CAD Large orange yellow tonsils & muscle atrophy Recurrent peripheral neuropathies HYPO LIPOPROTEINEMIAS (Decreased lipoproteins in the blood)

24. Thank you