IMED1003 - Cholesterol Distribution (2)

Distribution

Sources

- Cholesterol absorbed from diet (enterocytes)

- Cholesterol is endogenously synthesised (hepatic, extrahepatic tissues)

- Distribution between tissues via bloodstream requires lipoproteins

Lipoproteins: Structure

SURFACE (SHELL):

- Phospholipids

- Proteins: recognition by receptors, cofactors, enzymes

- Cholesterol

CORE:

- esterified lipids (TG, CE)

- Fat-soluble vitamins

Lipoproteins vary in composition

- Surface (shell): different proteins, serve different functions

- Core: different composition of esterified lipids

- As lipoproteins circulate, contents is taken up by tissues

- This changes composition of lipoproteins, generates lipoprotein "remnants"

3 Pathways of Cholesterol Distribution (NAMING ONLY)

- Exogenous Pathway

- Endogenous Pathway

- Reverse Transport Pathway

Exogenous Pathway (Cholesterol Distribution)

- enterocytes absorb cholesterol, secrete chylomicrons (85% TG)

- Chylomicrons transported through capillaries - TG depleted

- Lipoprotein lipase: Liberates FFA for use by peripheral tissues

- Chylomicron becomes chylomicron remnant (taken up by liver. The cholesterol from membrane and cholesteryl esters from core

- as the chylomicrons move through the bloodstream lipoprotein lipase triglycerides are depleted from the chylomicrons, liberates FFA

- CM remnant still has cholesterol in membrane and cholesteryl esters in core

Endogenous Pathway (Cholesterol Distribution)

- liver synthesises cholesterol

- esterifies C as CE, packages CE into VLDL, secretes into bloodstream

- Lipoprotein lipase: liberate FFA from VLDL

- VLDL becomes LDL

- LDL is rich in free (8%) and esterified cholesterol (37%)

- LDL distributes cholesterol to peripheral tissues (adrenal glands, gonads, muscle, adipose)

- LDL absorbed by liver, and process repeats

- once the IDL is formed FFA are liberated again and LDL is formed (highest conc. of cholesterol)

Regulation of cellular cholesterol concentrations: LDL receptor

- Cholesterol within LDL is absorbed by via the LDL receptor

- Regulation of LDL Receptor: high intracellular cholesterol levels, inhibit transcription LDLR gene, Decreased LDL receptor protein, Decreased cholesterol uptake

- Cells import cholesterol appropriate to requirements

- even hypothyroidism decreases activity of receptor

- detection of the LDL begins the receptor mediated endocytosis of LDL into the cell

- high intracellular cholesterol levels inhibits transcription LDLR gene, which means that there are less LDL recptor protein on membrane, hence decreased cholesterol uptake

Atherosclerosis: High [LDL] in bloodstream

- Atherosclerosis results in narrowing of blood vessels.

- this is a major cause of heart attack and stroke

- results from high plasma LDL concentrations

- hgih conc of LDL means that a plaque starts to form (which bulges and makes the blood vessel narrower)

- stroke or heart attack happens when this narrowing causes reduced blood flow to heart and brain

Reverse Cholesterol Transport

- Scavenges lipids in circulatory system

- HDL scavenges free cholesterol from: Extrahepatic tissues, remnant lipoproteins, foam cells growing atherosclerotic plaques

- HDL surface: Lecithin-cholesterol acyl transferase (LCAT): forms cholesteryl esters. the co-factor is ApoA-I

- HDL transports cholesterol back to the liver

- basically the liver secretes an empty HDL particle which scavenges free cholesterol from extrahepatic tissues etc.

- when empty HDL takes up cholesterol they become Nascent HDL

- this nascent HDL also scavenges cholesterol from Foam cells (this restricts growth of aterosclerotic plaque)

- HDL particle is escorted back to liver where it is absorbed

ABC Transporters

- export free cholesterol from cells

- ABC: ATP-Binding Cassette Transporters

- ABCA1: most cells

- ABCG1: macrophages, foam cells