erstein and Fagan, 1966). The latter is converted to isopentenyl pyrophosphate, which is polymerized and Southwestern Medical Center Dallas, Texas 75235 modified to form the 27 carbons of cholesterol. Cholesterol accumulation lowers the activity of HMG CoA reductase and several other enzymes in the cholesterol biosynthetic pathway, thereby limiting the production Animal cells must regulate their biosynthetic pathways of cholesterol (reviewed in Goldstein and Brown, 1990). so as to produce the required amounts of end-productsThe importance of the cholesterol feedback system without risking overproduction. Such control is particuto human health was established by the finding that larly important in cholesterol homeostasis because chodiets rich in cholesterol and saturated fatty acids raise lesterol must be supplied for many cellular functions, blood cholesterol levels and cause heart attacks (Keys, including two recently recognized ones: formation of 1975). In addition to suppressing synthesis of cholescaveolae (Smart et al., 1994; Murata et al., 1995) and terol, high cholesterol diets act through the feedback covalent modification of embryonic signaling proteins system to reduce the liver's uptake of cholesterol by (Porter et al., 1996). Excess cholesterol must be avoided suppressing production of receptors for low density because it forms solid crystals that kill cells. Excess lipoproteins (LDL), thus causing these atherogenic parcholesterol in the bloodstream is also lethal because it ticles to accumulate in blood (Spady et al., 1993; Goldstein deposits in arteries, initiating atherosclerosis (Small and et al., 1995). Conversely, the most potent cholesterol-Shipley, 1974). End-product regulation of cholesterol lowering drugs, the HMG CoA reductase inhibitors, metabolism is achieved predominantly through represexploit the feedback system by blocking cholesterol sion of transcription of genes that govern the synthesis synthesis, thereby reducing the liver's content of cholesof cholesterol and its receptor-mediated uptake from terol and increasing its production of LDL receptors plasma lipoproteins (Goldstein and Brown, 1990). (Brown and Goldstein, 1986;. As an end-product repressor, cholesterol presents aThe SREBPs, which regulate transcription of HMG special problem because it is an insoluble lipid that CoA reductase, also regulate transcription of genes resides almost exclusively in cell membranes. How does encoding many other enzymes in the cholesterol biosynthe cell sense the level of a membrane-embedded lipid, thetic pathway, including HMG CoA synthase, farnesyl and how is that information transmitted to the nucleus diphosphate synthase, and squalene synthase (Goldstein to regulate transcription? Answers are emerging from and Brown, 1990; Osborne, 1995; Guan et al., 1995; studies of a novel family of membrane-bound transcrip- Ericsson et al., 1996b). The SREBPs also regulate the tion factors called sterol regulatory element binding pro-LDL receptor, which supplies cholesterol through recepteins (SREBPs) th...
