cholesterol

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.

Together with sphingolipids, cholesterol is enriched in membrane microdomains termed lipid rafts, which function in cholesterol transport, endocytosis and signal transduction.

Extracellular transport of cholesterol is mediated by ApoE (APOE).

Cellular cholesterol homeostasis is maintained through activation of the designated sterol regulatory element binding proteins and liver X receptor transcriptional pathways.

Biosynthesis

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).

Pathology

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

See also

 cholesterol metabolism
 cholesterol biosynthesis
 cholesterol transport
 high-density lipoprotein cholesterol
 biliary acids metabolism
 cholesterol storage diseases
 cholesterol accumulation
 cholesterol crystals
 lipid rafts

References

 Norlin M, Wikvall K. Enzymes in the conversion of cholesterol into bile acids. Curr Mol Med. 2007 Mar;7(2):199-218. PMID: 17346171

 Anderson RG. Joe Goldstein and Mike Brown: from cholesterol homeostasis to new paradigms in membrane biology. Trends Cell Biol. 2003 Oct;13(10):534-9. PMID: 14507481

 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

 Oram JF. Molecular basis of cholesterol homeostasis: lessons from Tangier disease and ABCA1. Trends Mol Med. 2002 Apr;8(4):168-73. PMID: 11927274

 Elina Ikonen. Cellular cholesterol trafficking and compartmentalization. Nature Reviews Molecular Cell Biology 9, 125-138 (February 2008) (Link)