Alipoproteins
ApoB-100 associated lipoproteins are VLDL and LDL and bind to LDL receptor
which receptor does the ApoB- 100 binds to ?
ApoE is associated with VLDL, HDl and chylomicrons and triggers clearance of clearance of VLDL and chylromicrons remnants and associated with Alzheimer disease
Whats the lipo protein associated with ApoE and whats its respective disease?
Regulatory enzyme HMG-CoA reductase – Active (unphosphorylated) and inactive (phosphorylated form)
how is cholesterol regulated?
Heart disease is the #1 killer in the USA
• Excess cholesterol (LDL) in the blood results in atherosclerosis, (clogging of blood vessels)
• Inheritable hypercholesterolemia causes severe atherosclerosis in childhood (LDL is high, HDL is low)
What's cholesterol and heart disease ?
• excess FAs results in packaging of VLDL in the liver • Transport from the liver to muscle and adipose tissue - uptake of fatty acids – Myocytes oxidize FAs to generate energy – Adipocytes store FAs in lipid droplets – Loss of triacylglycerols generates IDLs and LDLs • Associated apolipoproteins – apoB-100 (large protein; binds to LDL receptor) – apoC-I - III, apoE • Removal of VLDL remnants via apoE in the live
whats VLDL ?
ApoC-1 is associated with VLDL and LDL and it activtates lipo protein lipase ?
Which lipo proteins is ApoC-1 associated with and whats the function of it ?
contain high proportion of triacyglycerols
• transporter for dietary fatty acids to tissues for consumption or storage
• largest and least dense lipoproteins
• synthesized in the ER in epithelial cells lining the small intestine
• Associated apolipoproteins – apoB-48 (unique to this class) – apoE – apoC-II (activates protein lipase C in capillaries of various tissues e.g.adipose, heart) • Removal from blood via apoE receptors in the liver
What are chylomicrons?
promote HMG-CoA reductase degradation
– inhibit HMG-CoA reductase transcription
– activate ACAT which increases esterification of cholesterol for storage
– reduce transcription of the gene encoding the LDL receptor => less uptake of cholesterol from the blood
what does high level of cholesterol promote ?
HMG-CoA reductase is the regulatory enzyme in the cholesterol synthesis pathway
• Lovastatin and compactin inhibit HMG-CoA reductase
what's the therapy of cholesterol regulation?
When VLDL are released from the liver they are nascent particles and must obtain Apo CII from circulating HDL before degradation of TAG. • Apo CII is required for lipoprotein lipase activity. • VLDL also receive Apo E from HDL
whats the metabolism of VLDL?
ApoC-11 is associated with VLDL, HDL and chylomicrons and it inhibits lipoprotein lipase .
which lipoproteins is ApoC-11 associated with and whats the desired function?
excess FAs results in packaging of VLDL in the liver
• Transport from the liver to muscle and adipose tissue - uptake of fatty acids –
Myocytes oxidize FAs to generate energy – Adipocytes store FAs in lipid droplets – Loss of triacylglycerols generates IDLs and LDLs
• Associated apolipoproteins – apoB-100 (large protein; binds to LDL receptor) – apoC-I - III, apoE
• Removal of VLDL remnants via apoE in the liver
2. glucagon stimulates phosphorylation
3. insulin promotes dephosphorylation
what does glucagon and insulin?
Synthesis of HDL begins in the liver and small intestine • Contains the enzyme lecithin-cholesterol acyl transferase (LCAT) => formation of cholesteryl esters from lecithin + cholesterol • Returns to the liver where it unloads the cholesterol, some of which is then turned into bile salts • Taken up in the liver via receptor mediated endocytosis • Also binds to SR-BI receptors in hepatic tissues and adrenal gland => partial transfer of cholestero
whats HDL proteins?
As VLDL pass through the circulation the structure is altered through: 1.TAG is removed by LPL causing shrinkage and increased density. 2.Surface components PL, C and Apo C & E, are transferred to HDL 3.CE’s are transferred from HDL to VLDL in a reaction that at the same time transfer TAG or PL from VLDL to HDL (by cholesteryl ester transfer protein
whats the metabolism of VLDL about?
ApoC-111 is associated with VLDL, HDL and chylomicrons
ApoC-111 is associated with which lipoproteins ?
Derived from VLDLs upon loss of triacylglycerols
• Very rich in cholesterol & cholesteryl esters
• Transport of cholesterol and their esters to extrahepatic tissues
• apoB-100 receptor mediated uptake
• associated apolipoproteins – predominantly apoB-100
What are LDL proteins?
HMG-CoA reductase -P
whats the inactive form as it relates to the regulation of cholesterol ?
apoB-100 (small green oval) binds to LDL receptor 2. receptor binding triggers endocytosis and formation of endosome (blue) 3. endosome fuses with lysosome 4. digestion of LDL liposome and relocation of receptor to the surface
whats receptor meditated endocytosis
The lipoprotein remnants are then degraded by lysosomal enzymes, releasing: • Cholesterol • Amino acids • Fatty acids • Phospholipids. • These can be recycled by the cell
LDL are regulated by?
ApoD is associated with HDL
ApoD is associated with which lipoprotein?
circulating reservoir of Apo CII, that is transferred to VLDL and chylomicrons and activates lipoprotein lipase. • Removes free (unesterified) cholesterol fro extrahepatic tissues and esterifies it, using PCAT or LCAT • Transfer cholesteryl esters to VLDL and LDL in exchange for TAG • Carries CE to liver, where HDL is degraded and cholesterol released. 33 34 Functions of HDL Particles • HDL particles are excellent acceptors of unesterified cholesterol, both from cell membranes and other circulating lipoproteins • Once free cholesterol is taken up, it is immediately esterified by PCAT. • PCAT is activated by Apo A-1 of HDL. • The FA from C#2 of phosphatidyl choline is transferred directly to cholesterol. • Lysophosphatidyl choline is formed. 34 35 Functions of HDL Particles • The cholesteryl ester formed is hydrophobic and is thus trapped in HDL (cannot be deposited to membranes) • The only way it is transferred is from HDL to VLDL or LDL by the CE transfer protein. • It remains in LDL until the particle is taken up by cell. • About 2 /3 of plasma cholesterol is esterified with Fatty Acid.
What are the functions of HDL particles ?
HMG-CoA reductase
whats the active from of the HMG- CoA reductase as it relates to cholestrol regulation ?
• Derived from VLDLs upon loss of triacylglycerols • Very rich in cholesterol & cholesteryl esters • Transport of cholesterol and their esters to extrahepatic tissues • apoB-100 receptor mediated uptake • associated apolipoproteins – predominantly apoB-100
whats VLDL proteins?
HMG CoA reductase activity is decreased, de novo synthesis of cholesterol decreases. 2.If cholesterol is not required for structural or synthetic purpose it is esterified by ACAT (acyl CoA: cholesterol acyltransferase) and stored for future use
whats the effect of chylomicron remnants, HDL and LDL cholesterol on cellular cholesterol?