Lipidomics Gateway (1 May 2009) [doi:10.1038/lipidmaps.2009.3]
Try to do too much and something is bound to go wrong. After two centuries of research, cholesterol has risen to both fame and infamy; essential to life yet integral to disease, intertwined in ever-expanding aspects of animal biology and pathology.
First detected in human gallstones in the late eighteenth 1 century and purified early in the nineteenth 2 , cholesterol became a household name before the close of the last millennium. With a research history that includes a sprinkling of Nobel prizes, cholesterol now appears in the title of over 40,000 papers listed in PubMed and returns more than 27 million hits on Google. Why all this interest? Cholesterol is essential to membrane function, has a complex system of regulation and, when deregulated, contributes to pathogenesis of some of the biggest human killers today, including stroke, heart disease and cancer.
Mammalian cell membranes contain varying proportions of cholesterol depending on organelle and cell type. These levels are tightly controlled by lipid transfer, through both vesicular and protein-bound pathways. With its rigid sterol backbone, cholesterol preferentially locates among saturated membrane lipids that have straight, elongated hydrocarbon chains rather than among kinked, unsaturated species. The presence of cholesterol in the membrane increases lateral ordering of lipids, reducing permeability and fluidity and potentially restricting diffusion of membrane proteins. Its distribution is not uniform within a membrane: regions of high cholesterol and corresponding low fluidity are termed lipid rafts. These areas act as platforms for the assembly of signaling complexes within the membrane and have been implicated in the development of numerous disease processes, notably cancer 3 4 .
Cholesterol synthesis begins with acetate and involves several intermediates. In 1933, Rudolf Schoenheimer showed that feeding cholesterol to mice decreased its synthesis, the first demonstration of product feedback inhibition of a biosynthetic pathway 5 . The molecular basis of this regulation was set out by Michael Brown and Joseph Goldstein, earning them the Nobel Prize in Physiology and Medicine in 1985. A key irreversible step of cholesterol synthesis is catalyzed by HMG-CoA reductase. Transcription of the HMG gene is controlled by SREBPs (sterol regulatory element binding proteins), transcription factors that bind sterol regulatory elements. SREBPs are only able to enter the nucleus when cholesterol levels fall: at other times they are tied up in a complex that includes Scap (SREBP-cleavage activating protein), an escort protein with a cholesterol-binding motif that senses cellular cholesterol levels. The SREBP pathway is now implicated in multiple regulatory aspects of lipid formation and metabolism 6 .
Owing to its limited solubility in water, cholesterol is transported in blood in spherical particles, lipoproteins. The lipoprotein outer layer is formed of amphiphilic cholesterol and phospholipid molecules, studded with proteins, surrounding a hydrophobic core of triglycerides and cholesterol esters. The types of lipoproteins are named for their density and they are specifically targeted to cells by distinct apolipoproteins on their surface that bind to specific receptors. Low density lipoprotein (LDL) contains the highest level of cholesterol. LDL receptors in peripheral tissues bind LDL, triggering its endocytosis, lysosomal targeting and hydrolysis. When cells have abundant cholesterol, LDL receptor synthesis is inhibited by the SREBP pathway. When cholesterol levels become deregulated, more LDL exists in the blood than can be taken up by LDL receptors. Excess LDL is oxidized and taken up by macrophages, forming foam cells that can become trapped in the walls of blood vessels. The end result is an atherosclerotic plaque, the major cause of heart attacks and strokes. Although LDL levels correlate with heart attack risk, high density lipoprotein (HDL) has an inverse ratio of risk because these particles transport cholesterol to the liver for excretion. Modern cholesterol tests distinguish the LDL/HDL ratio as well as the overall level 7 .
Fourcroy, A. Examen chimique de la substance feuilletée et cristalline continue dans les calculs biliaires; et de la nature des concrétions crystiques cristallisées.
Ann. Chim. 3, 242-252 (1789).
Chevreul, M.E. Des corps qu'on a appelés adipocire, c'est à dire, de la substance cristallisée des calculs biliaires humains, du spermaceti et de la substance grasse des cadavres.
Ann. Chim. 95, 5-50 (1815).
Ikonen, E. Cellular cholesterol trafficking and compartmentalization.
Nature Rev. Mol. Cell Biol. 9, 125-138 (2008). doi:10.1038/nrm2336
Di Vizio, D, Solomon, K.R. & Freeman, M.R. Cholesterol and cholesterol-rich membranes in prostate cancer: an update.
Tumori 5, 633-639 (2008).
Schoenheimer, R. & Breusch, F. Synthesis and destruction of cholesterol in the organism.
J. Biol. Chem. 103, 439-448 (1933).
Brown, M.S. & Goldstein, J.L. Cholesterol feedback: from Schenheimer's bottle to Scap's MELADL.
J. Lipid Res. 50, S15-S27 (2009). doi:10.1194/jlr.R800054-JLR200
Barter, P. et al. HDL Cholesterol, Very Low Levels of LDL Cholesterol, and Cardiovascular Events.
N. Engl. J. Med. 357, 1301-1310 (2007). doi:10.1056/NEJMoa064278