Post on 16-Jul-2015
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
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