Lecture 19 and 20:Cholesterol transport/ cholesterogenesis

chylomicron<VLDL<IDL<LDL<HDL

chylomicron>VLDL>IDL>LDL>HDL

Dietary triacylglycerides. The main role of chylomicrons is to bring dietary TGs from the intestine to peripheral tissues like muscle and adipose

Assembled in the intestine, secreted by enterocytes

Within the intestinal mucosal celll, the FFAs and MG are reassembled into TGs which are them packaged into chylomicrons. The chylomicrons then travel to tissues such as muscle and adipose where they are acted upon by lipoprotein lipase released FFA's again.

LL is most present in adipose and muscle. IT is expressed on the endotheial surface of blood capillaries bound to heparan sulfate proteoglycans. IT's action requires apo CII.
Activity in adipose is induced by insulin, activty in the muslce remains high and is increased under catabolic conditions.

b-48 and A are original
Aquired from HDL:
CII-lipoprotein lipase
E-LDL receptor, hepatic lipase

Residues TGs and the dietary cholesterol are now carried in the chylomicron remnant. The CR is taken up in the liver via the LDL receptor and heaptic lipase binding apo E. In the liver, the particles are endocytosed and catabolized

Contents=leftover TGs, dietary cholesterol
fate:
1. secrete into bile
2. change into bile acids
3. incorporate into nascent lipoproteins

rich it TGs
the role of VLDLs is to transport endogenous TGs from the liver to peripheral tissues
some cholesterol and cholesterol esters

apoB-100=LDL receptor (low affinity)
apo CII-lipoprotein lipase
ApoE-LDL receptor (high affinity) heaptic lipase

assembled in the liver, secreted by hepatocytes.

pathway for export from hepatocytes of excess endogenous TGs derived from lipgenesis, plasma FFA, and chylomicron remnants which would otherwise be stored in cdells

VLDL particles are packaged in the liver with TGs, cholesterol and cholesterol esters. The VLDLs leave the liver and are hydrolysed by liporportein lipase (activated by apo CII) and release FAs. The remnant, called IDL is removed fom the circuation by hepatocytes via the LDL receptor binding to apo E.

cholesterol esters because the TGs were delievered by VLDL to other tissues via lipoprotein lipase

B-100
C-II-one left over after VLDL bound to lipoprotein lipase
E-to bind LDL receptor and hepatic lipase

VLDL becomes IDL after removal of TGs by lipoprotein lipase interacting with apo C. The IDL can be taken up by the liver via the apoE binding to the LDL receptor or converted into LDL.
To convert to LDL another apo C and the apo E lipoproteins are given back to HDL which converts the moleule to LDL which only expressed B-100

cholesterol esters

apoB-100, binds w/ low affinity to LDL receptor

derived from IDL follwoing removal of TG by hepatic lipase (via apoE)

Hepatic lipase binds apo E
Apo E is expressed by Chylomicrons (aquired from HDL), VLDL, and IDL
(all except LDL which only expresses B-100)

1. transport cholesterol to peripheral tissues
2. regulate de novo cholesterol synthesis at peripheral tissues

binds with low affinity (compared to IDL) via apoB-100

apoA-1-ABCA1, receives cholesterol, activates LCAT
apoC-II-binds lipoprotein lipase
ApoE-binds heaptic lipase and LDL receptor

1. originates in liver an small intestine
2. gains cholesterol via ABCA1 delivering to ApoA-1
3. Activated by ApoA-1, LCAT delivers cholesterol esters

scavenger receptor B1

HDL promotes the efflux of cholesterol from macrophage foam cells in the aterial wall back to the liver

-synthesis of cholesterol esters
-acts on HDL to esterify free cholesterol with a fatty acyl residue of lecithin
-the cholesterol esters are then trasfered via CETP from HDL to ther lipoproteins such as LDL and VLDL.
-this action works to remove cholesterol from HDL as cholesterol esters so that HDL can go pick up more cholesterol

transfers cholesterol esters from HDL to LDL and VLDL

transfers TGs from other lipoproteins to HDL

-ABCA1 via apoA-1 transfers cholesterol esters to HDL and LCAT esterifies it
-SR-B1 removes cholesterol esters from HDL into hpeatic/steroidogenic cells
-This depletes HDL of cholesterol esters
-"empty" HDL goes back to the blood stream to extract mroe lipid
-in the liver, the cholesterol esters are hyrdrolyzed to cholesterol which is then excreted

3 or more of the followingt
hypertriglyceridemia, low HDL, hypertension, increased waist circumfrence, elevated fasting glucose

-free FFA levles increase
-excess lipids lead to stabilization of apo B, the major lipoprotein of VLDL
-there is also lack of promotion of apoB degradation due lack of insulin response
-decreased lipoprotein lipsae activity, the major clearer of VLDL
-thus the combination of increased FFA and too much apoB leads to more VLDL

lipoprotein lipase is the major mediator of VLDL clearance. If it's activity is decreased, VDL and IDL increase.

normally CETP transters colesterol esters from HDL to chylomicrons and VLDL in exchange for TGs. With insulin resistance alters this leading to cholesterol enriched VLDL/ LDL/ VLDL remants and triglyceride enriched HDL

TG enriched HDL is a better substrate for hepatic lipase. The HDL is hydrolysed and it's circulating levels decrease

-lack of insulin signaling decreases transport of insulin into peropheral tissues
-the elevated plasma glucose is sensed by the B cells which respond by producing more insulin
-continued stimulation of the B cells leads to hypertrophy, failure to secrete insulin normally, and ultimatley B cell failure

Ligand-activated transpription factors.
Once they are bound to their ligans, they form heterodimers with the nuclear receptor and modulate gene expression. PPARa and PPARg are targets for insulin resistance treatment

Fibrates target PPARa which is a ligand activated transcription factor. The fibrates mimic the normal ligand (agonists) of PPARa and stimulate expression of beta oxidation genes. This decreates TGs and VLDL whine increases HDL synthesis and ApoA1 expression.

Thiazolidinediones target PPARgamma and function as agonisist. They lower glucose and enhance insulin sensitivity by upregulating the SRB1 receptor.

1. elevated LDL
2. deposite of LDL derived cholesterol in the tendons and skin
3. inheritance as an autosomal dominant trait with gene dosage effect

a mutation in the gene encoding the LDL receptor

1. inhibit HMG CoA reductase
2. activate ACAT (esterifies and stores cholesterol with the cell)
3. inhibit synthesis of LDL receptor

-regulated by SREBP membrane bound transcription factors
-when cholesterol is low, SCAP releases the SREBP which goes on to bind an SRE in the nuleus and express the LDL receptor
-when choleseterol is high, it binds to SCAP and prevents the release of SREBP

1. limit LDL production by enhancing the removal of IDL (the receptor bind to IDL with higher affinity than LDL)
2. Enhancec LDL degradation

The cholesterol in the diet binds to SCAP and prevents release of SREBP. This decreases the expression of heaptic LDL receptors which leads to increased plasma LDL.

a heterozygote has one heathly LDL receptor gene so therapies are aimed at increasing expression by inducing a cholesterol deficiency
1. Bile acid binding resins to increase excretion of cholesterol expression by the liver
2. HMG CoA reductase inhibitors to limit de novo synthesis
3. Diet low in cholesterol and fat

Homozygotes have no normal receptor
1. LDL aphresis
2. liver transplantation
3. gene therapy