Cholesterol and the SREBP pathway

Article By:

Rawson, Robert B. Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas.

Last reviewed:2009

Cholesterol is an essential component of mammalian cell membranes. (In general, cholesterol and structurally related compounds made by plants and fungi are collectively termed “sterols.” Virtually all eukaryotic organisms require some sort of sterol in their membranes, and the presence of sterols is evidence for the existence of eukaryotes in the fossil record.) Without sufficient cholesterol, membranes cannot work properly and cells die. Conversely, too much cholesterol is also lethal to cells and organisms, and high levels of cholesterol in blood are a major cause of atherosclerosis in humans. Therefore, cells and organisms must maintain an exquisite balance between the cholesterol supply and cellular demand. This balancing act is regulated at just about every conceivable level, from gene transcription to enzyme activity. The global coordination of cellular cholesterol metabolism, however, is largely effected at the level of transcription of the genes of cholesterol synthesis and uptake [for example, the low-density lipoprotein (LDL) receptor, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, and HMG CoA synthase] through the action of the sterol regulatory element binding proteins (SREBPs). In mammals, there are three different SREBPs encoded by two different genes. SREBP-1a and -1c result from the utilization of alternative transcription initiation sites of the SREBF-1 (sterol regulatory element binding transcription factor-1) gene; SREBP-2 is encoded by the SREBF-2 gene. In adult animals, SREBP-1c and -2 are the predominant species, with the former preferentially targeting genes of fatty acid metabolism and the latter preferentially targeting genes of cholesterol metabolism.

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