Pioneering work of Brown and Goldstein (1997) over the last 10 years has clearly shown that cholesterol regulates its own metabolism. Cholesterol plays an important role in growth because it is a component of cell membranes and steroids. The cell has the capacity to regulate its uptake of cholesterol through the low density lipoprotein (LDL) receptor (LDLR), as well as to regulate de novo synthesis of cholesterol. (Figure 5–2). Low intracellular cholesterol levels prompt a cellular response that leads to an induction in both the LDLR and the enzymes responsible for cholesterol synthesis. As intracellular cholesterol levels increase, this process is reversed. These changes in cholesterol metabolism are due, at least in part, to the effect of cholesterol on the nuclear content of a family of specific transcription factors called sterol regulatory element binding proteins (SREBP). Three SREBP subtypes have been described (i.e., SREBP1a, SREBP1c, and SREBP2). SREBPs are helix-loop-helix transcription factors that bind at specific cis-regulatory elements called sterol regulatory elements (SRE) in the promoters of several genes involved cholesterol synthesis, cholesterol uptake, and fatty acid synthesis. Binding of SREBP to SRE induces transcription of specific genes, leading to an increase in the mRNA and corresponding protein.
SREBPs are synthesized as ~125 kd precursor proteins (pSREBP) tethered to the endoplasmic reticulum and golgi membranes. Specific proteases digest the precursor to generate a 65 kd form of SREBP (nSREBP) that travels to the nucleus where it binds SREs. Cholesterol regulates the nuclear content of