LIPO PROTEIN METABOLISMLIPO PROTEIN METABOLISM

Dr. V. Siva Prabodh Dr. V. Siva Prabodh MDMDProfessorProfessor

Dept. of BiochemistryDept. of Biochemistry NRI Medical CollegeNRI Medical College

LipoproteinsLipoproteins

These are molecular complexes which contains These are molecular complexes which contains Lipids & proteinsLipids & proteins

FunctionFunction: : Transports Lipids in blood.Transports Lipids in blood.

Classification of LipoproteinsClassification of Lipoproteins

Five Major classesFive Major classes

1)1) ChylomicronsChylomicrons

2)2) VLDLVLDL

3)3) LDLLDL

4)4) HDLHDL

5)5) FFA with albuminFFA with albumin

Lipo proteins are seperated by Lipo proteins are seperated by Ultra Ultra centrifugation/Electrophoresiscentrifugation/Electrophoresis

1)1) ChylomicronsChylomicrons:: Synthesized in the Intestine. Synthesized in the Intestine.

Transport Exogenous lipids (Dietary Lipids)Transport Exogenous lipids (Dietary Lipids)

99% Lipids, 1% protein, Density very less.99% Lipids, 1% protein, Density very less.

2)2) VLDL :VLDL : Produced in the Liver & Intestine Produced in the Liver & Intestine

Transport Endogenous lipidsTransport Endogenous lipids

3) 3) LDLLDL : : Formed from VLDL in blood Formed from VLDL in blood Transport cholesterol from Liver to Transport cholesterol from Liver to other tissues. other tissues.

4) 4) HDLHDL : : Mostly synthesized in Liver Mostly synthesized in Liver

Transport cholesterol from Transport cholesterol from peripheral tissues to Liver (Reverse peripheral tissues to Liver (Reverse

cholesterol transport) cholesterol transport)

5) 5) FFA with albuminFFA with albumin: Each molecule : Each molecule of albumin hold 20-30 molecules of of albumin hold 20-30 molecules of FFA. FFA.

ApolipoproteinsApolipoproteins

• Structural determinants of lipoproteins

• Enzyme cofactors

• Ligands for binding to lipoprotein receptors

ApoproteinsApoproteins

The protein forms of Lipoproteins are known as The protein forms of Lipoproteins are known as Apolipoproteins or Apoproteins.Apolipoproteins or Apoproteins.

Functions: Functions:

1)1) Structural component – Structural component – apo A, apo Bapo A, apo B4848, apo B, apo B100100

apo Capo C

2)2) Recognizes surface receptors – Recognizes surface receptors – apo E, apo Bapo E, apo B100100

3)3) Activate Lipoprotein Lipase – Activate Lipoprotein Lipase – apo C IIapo C II

ChylomicronsChylomicrons

VLDLVLDL

LDLLDL

Low density Lipoprotein is formed from VLDL and the Low density Lipoprotein is formed from VLDL and the Intermediate is IDL.Intermediate is IDL.

LDL contain high cholesterol and less TAGLDL contain high cholesterol and less TAG. .

FunctionFunction:– Supply cholesterol to extra hepatic tissues.:– Supply cholesterol to extra hepatic tissues.

LDL particles bind to specific receptors over the cell LDL particles bind to specific receptors over the cell membrane which are membrane which are clathrin coated pitclathrin coated pitApo BApo B100100 recognizes the receptors over the cell membrane recognizes the receptors over the cell membrane

Deficiency of LDL receptors leads to Increased circulating Deficiency of LDL receptors leads to Increased circulating LDL and hence cholesterol increases LDL and hence cholesterol increases

Eg: Type IIa hyperbeta lipoproteinemia.Eg: Type IIa hyperbeta lipoproteinemia.

From Medical Biochemistry, Baynes & Dominiczak, Mosby, 1999.

Enzymes and Transfer ProteinsEnzymes and Transfer Proteins

• LCAT (Lecithin:Cholesterol Acyltransferase)

• Formation of cholesterol esters in lipoproteins

• ACAT (Acyl-CoA:Cholesterol Acyltransferase)

• Formation of cholesterol esters in cells

• CETP (Cholesterol Ester Transfer Protein)

HDL HDL

High density Lipoproteins (Three types HDLHigh density Lipoproteins (Three types HDL11, HDL, HDL2, 2, HDLHDL33))

Cholesterol is transported from Extra hepatic tissue to Liver Cholesterol is transported from Extra hepatic tissue to Liver where it is excreted in the form of bile.where it is excreted in the form of bile.

Anti – atherogenicAnti – atherogenic, , Good cholesterolGood cholesterol

Intestinal cells synthesize HDL and release into blood.Intestinal cells synthesize HDL and release into blood.

LCAT:LCAT: Lecithin cholesterol Acyl transferases, transfer Lecithin cholesterol Acyl transferases, transfer PUFA from Lecithin to cholesterol to form cholesterol ester, PUFA from Lecithin to cholesterol to form cholesterol ester, which moves into interior of HDLwhich moves into interior of HDL

APO A IAPO A I activates LCAT activates LCAT

The HDL with more cholesterol are taken up by Liver cells, The HDL with more cholesterol are taken up by Liver cells, and cholesterol is released into Liver. (Reverse cholesterol and cholesterol is released into Liver. (Reverse cholesterol transport)transport)

HYPER LIPOPROTEINEMIASHYPER LIPOPROTEINEMIAS

HLP-Phenotypes (Fredrickson, WHO) Lipoproteins Lipids Defect I Chylomicron TG LP lipase IIA LDL LDL-C LDL-receptor IIB LDL + VLDL LDL-C, TG HMG.CoA reductase III IDL TC, TG Apo-E deficiency IV VLDL TG VLDL overproduction V Chylomicron + VLDL TG Apo-C2 deficiency

From Medical Biochemistry, Baynes & Dominiczak, Mosby, 1999.

Familial hypercholesterolemia (type II a)

Receptor-mediated uptake of LDL is one of the best understood examples of receptor-mediated endocytosis. LDL is a protein-lipid complex that transports cholesterol-fatty acid esters in the blood stream. LDL normally supplies cholesterol to cells. Defects in the endocytic process result in high blood levels of LDL. High LDL predisposes individuals for atherosclerosis.

1

Apo-B100

Apo-E

Dominantly inherited disorder

- deficiency in a cell surface LDL-R (the receptor regulates LDL degradation and cholesterol synthesis)

high cholesterol (since birth) high LDL-C leads to premature atherosclerosis, xanthomas

of skin and tendons

Total Cholesterol>240mg/dl

LDL>190 mg/dl

XanthomasXanthomasraised lesions related to raised lesions related to hyperlipidemiahyperlipidemia

Eruptive Xanthomas-generally associated withhypertriglyceridemia

Xanthomas of the eyelid-generally associated withhypercholesterolemia

Case StudyCase Study– familial hypercholesterolemia– familial hypercholesterolemia

8 yr girl8 yr girl Admitted for heart/liver transplantAdmitted for heart/liver transplant

HistoryHistory CHD in familyCHD in family 2 yr xanthomas appear on legs2 yr xanthomas appear on legs 4 yr xanthomas appear on elbows4 yr xanthomas appear on elbows 7 yr admitted w/ MI symptoms7 yr admitted w/ MI symptoms

[TC] = 1240 mg/dl[TC] = 1240 mg/dl [TG] = 350 mg/dl[TG] = 350 mg/dl [TC]father = 355 mg/dl[TC]father = 355 mg/dl [TC]mother = 310 mg/dl[TC]mother = 310 mg/dl

2 wks after MI had coronary bypass surgery2 wks after MI had coronary bypass surgery Despite low-fat diet, cholestyramine, & lovastatin, [TC] = 1000 Despite low-fat diet, cholestyramine, & lovastatin, [TC] = 1000

mg/dlmg/dl

ThankThank youyou