Friday 14 November 2003
Definition: Cholesterol is an essential sterol lipid component of eukaryotic plasma and organelle membranes. It is particularly abundant in the brain as a major constituent of myelin.
Extracellular transport of cholesterol is mediated by ApoE (APOE).
About 20–25% of total daily cholesterol production occurs in the liver; other sites of high synthesis rates include the intestines, adrenal glands and reproductive organs.
Synthesis within the body starts with one molecule of acetyl CoA and one molecule of acetoacetyl-CoA, which are dehydrated to form 3-hydroxy-3-methylglutaryl CoA (HMG-CoA).
This molecule is then reduced to mevalonate by the enzyme HMG-CoA reductase. This step is an irreversible step in cholesterol synthesis and is the site of action for the statins (HMG-CoA Reductase Inhibitors).
All carbon atoms of cholesterol derive from reductive polymerizations from the simple building block acetate. The rate-limiting enzyme of the pathway is hydroxymethylglutaryl CoA reductase (HMG-CoAR), that is the target of statins.
HMG-CoAR catalyses the synthesis of mevalonate (mevalonic acid) and is under tight regulation. Six enzyme reactions convert mevalonate to squalene.
The first step committed towards cholesterol biosynthesis is the one catalysed by squalene cyclase, which results in the formation of lanosterol in a reaction that requires one molecule of O2 and thus depends on aerobic conditions.
A complex set of 20 reactions that consumes 10 additional O2 molecules yields cholesterol through sequential demethylations and reductions of double bonds.
The post-lanosterol steps of cholesterol biosynthesis have been divided into Bloch and Kandutsch–Russell pathways, which share the same enzymatic steps but are distinguished by the stage at which the C24 double bond is reduced.
Cholesterol can be fatty acylated to form cholesteryl esters in all cells (cholesteryl oleate is shown), or it can be oxidized to form oxysterols by enzymatic reactions or by auto-oxidation in all cells (25-hydroxycholesterol is shown) or oxidized to bile acids in hepatocytes only (this is relevant for the net elimination of sterols from the body; cholic acid is shown) or oxidized to steroid hormones in steroidogenic cells (pregnenolone is shown).
Axonal transport of cholesterol is defective in Niemann–Pick disease type C, and some recent reports suggest a role for cholesterol in Alzheimer disease.
cholesterol metabolism and Alzheimer disease
cholesterol metabolism and prostatic carcinoma
cholesterol metabolism and atherosclerosis
high-density lipoprotein cholesterol
biliary acids metabolism
cholesterol storage diseases
Kaul D. Cholesterol-receptor-mediated genomics in health and disease. Trends Mol Med. 2003 Oct;9(10):442-9. PMID: 14557057
Poirier J. Apolipoprotein E and cholesterol metabolism in the pathogenesis and treatment of Alzheimer’s disease. Trends Mol Med. 2003 Mar;9(3):94-101. PMID: 12657430