Lipoproteins

1. Lipoproteins • particles found in plasma that transport lipids including cholesterol • lipoprotein classes • chylomicrons: take lipids from small intestine through lymph cells • very low density lipoproteins (VLDL) • intermediate density lipoproteins (IDL) • low density lipoproteins (LDL) • high density lipoproteins (HDL)

2. Composition and properties of human lipoproteins most proteins have densities of about 1.3 – 1.4 g/mL and lipid aggregates usually have densities of about 0.8 g/mL

3. Lipoprotein structure

4. LDL molecule

5. The apolipoproteins • major components of lipoproteins • often referred to as apoproteins • classified by alphabetical designation (A-E) • the use of roman numeral suffix describes the order in which the apolipoprotein emerge from a chromatographic column • responsible for recognition of particle by receptors

6. LIPOPROTEINS • spherical particles with a hydrophobic core (TG and esterified cholesterol) • apolipoproteins on the surface • large: apoB (b-48 and B-100) • smaller: apoA-I, apoC-II, apoE • classified on the basis of density and electrophoretic mobility (VLDL; LDL; IDL;HDL)

7. Apoproteins of human lipoproteins • A-I (28,300)- principal protein in HDL • 90 –120 mg% in plasma; activates LCAT • A-II (8,700) – occurs as dimer mainly in HDL • 30 – 50 mg %; enhances hepatic lipase activity • B-48 (240,000) – found only in chylomicron • <5 mg %; derived from apo-B-100 gene by RNA editing; lacks the LDL receptor-binding domain of apo-B-100 • B-100 (500,000) – principal protein in LDL • 80 –100 mg %; binds to LDL receptor

8. Apoproteins of human lipoproteins • C-I (7,000) – found in chylomicron, VLDL, HDL • 4 – 7 mg %; may also activate LCAT • C-II (8,800) - found in chylomicron, VLDL, HDL • 3 – 8 mg %; activates lipoprotein lipase • C-III (8,800) - found in chylomicron, VLDL, IDL, HDL • 8 – 15 mg %; inhibits lipoprotein lipase • D (32,500) - found in HDL • 8 – 10 mg %; also called cholesterol ester transfer protein (CETP) • E (34,100) - found in chylomicron, VLDL, IDL, HDL • 3 – 6 mg %; binds to LDL receptor • H (50,000) – found in chylomicron; also known as b-2-glycoprotein I (involved in TG metabolism)

9. Type Association Function B48 Chylomicron Carry cholesterol esters Lacks LDL recpt binding domain B100 VLDL,IDL,LDL Binds LDL recpt. C-II Chyl. VLDL, IDL, HDL Activates LPL C-III Chyl. VLDL, IDL, HDL Inhibits LPL E Chyl. Remnant, VLDL, IDL Binds LDL recpt HDL A-1 HDL/Chylomicron LCAT activator (lecithin cholesterol acyltransferase)

11. Major lipoprotein classes • Chylomicrons (derived from diet) • density <<1.006 • diameter 80 - 500 nm • dietary triglycerides • apoB-48, apoA-I, apoA-II, apoA-IV, apoC-II/C-III, apoE • remains at origin in electrophoretic field

12. Chylomicron • formed through extrusion of resynthesized triglycerides from the mucosal cells into the intestinal lacteals • flow through the thoracic ducts into the subclavian veins • degraded to remnants by the action of lipoprotein lipase (LpL) which is located on capillary endothelial cell surface • remnants are taken up by liver parenchymal cells due to apoE-III and apoE-IV isoform recognition sites

13. Chylomicron metabolism

14. Major lipoprotein classes • VLDL • density >1.006 • diameter 30 - 80nm • endogenous triglycerides • apoB-100, apoE, apoC-II/C-III • prebeta in electrophoresis • formed in the liver as nascent VLDL (contains only triglycerides, apoA and apoB)

15. VLDL • nascent VLDLs then interact with HDL to generate mature VLDLs (with added cholesterol, apoC-II and apoC-III) • mature VLDLs are acted upon by LpL to generate VLDL remnants (IDL) • IDL are further degraded by hepatic triglyceride lipase (HTGL) to generate LDLs

16. VLDL metabolism

17. Major lipoprotein classes • IDL (intermediate density lipoproteins) • density: 1.006 - 1.019 • diameter: 25 - 35nm • cholesteryl esters and triglycerides • apoB-100, apoE, apoC-II/C-III • slow pre-beta

18. Major lipoprotein classes • LDL (low density lipoproteins) • density: 1.019 - 1.063 • diameter: 18-25nm • cholesteryl esters • apoB-100 • beta (electrophoresis) • < 130 LDL cholesterol is desirable, 130-159 is borderline high and >160 is high

19. Major lipoprotein classes • HDL (high density lipoproteins) • density: 1.063-1.210 • diameter: 5-12nm • cholesteryl esters and phospholipids • apoA-I, apoA-II, apoC-II/C-III and apoE • alpha (electrophoresis)

20. Functions of HDL • transfers proteins to other lipoproteins • picks up lipids from other lipoproteins • picks up cholesterol from cell membranes • converts cholesterol to cholesterol esters via the LCAT reaction • transfers cholesterol esters to other lipoproteins, which transport them to the liver (referred to as “reverse cholesterol transport)

21. Cholesterol and lipid transport by lipoproteins

22. Cholesterol and lipid transport by lipoproteins

23. Liver Dietary TG Apo B48 CE cholesterol Apo B48 CII TG/CE FFA FFA-FABP TG micelle A CIII chylomicron ER/golgi enterocyte Plasma

24. Plasma TG B48 FFA Oxidation CII TG/CE muscle Lipoprotein Lipase CIII chylomicron Lipoprotein Lipase B48 CII TG/CE FFA CIII E FFA Chylomicron remnant liver G3P Triglyceride storage adipose

25. Endogenous Lipid Transport

26. Plasma Dietary Carbohydrate LIVER glucose pyruvate Acetyl CoA B48 LDL receptor Acetyl CoA TG/CE mitochondria E TG Cholesterol (endogenous) CMr cholesterol (exogenous) B100 CE/TG VLDL FFA TG FFA VLDL

27. Cholesterol. In bile From liver LIVER Endogenous cholesterol B100 E CE/TG CII VLDL B100 E LDL receptor CE/TG IDL E B100 LPL CE FA LDL Extrahepatic tissue FFA muscle LDL receptor adipose

28. LDL Liver Dietary fat Bile salts Endogenous cholesterol extrahepatic tissue small intestine Exogenous cholesterol HDL chylomicrons reminants chylomicrons VLDL IDL capillaries Lipoprotein Lipase Lipoprotein Lipase FFA FFA Adipose, muscle

29. The End