Michael S. Brown, M.D.
How Cells Control Cholesterol
Our research is directed at unraveling the mechanism by which the SREBP pathway regulates cholesterol metabolism at the molecular, cellular, and whole body levels.
Sterol Regulatory Element Binding Proteins (SREBPs) are membrane-bound bHLH-Zip transcription factors that regulate the synthesis and uptake of cholesterol and fatty acids in animal cells. Two SREBPs, designated SREBP-1a and SREBP-2, predominate in cultured cells. The activities of both SREBPs are regulated by the sterol content of the cells. When cells are replete with sterols, the SREBPs remain bound to membranes of the endoplasmic reticulum and nuclear envelope and are therefore inactive. When cells are depleted of sterols, a two-step proteolytic process releases the active portions of the SREBPs, which enter the nucleus and stimulate transcription of genes in three pathways of lipid metabolism: 1) cholesterol biosynthesis (HMG CoA synthase, HMG CoA reductase, farnesyl diphosphate synthase, squalene synthase); 2) uptake of cholesterol and fatty acids from plasma (LDL receptor and lipoprotein lipase); and 3) fatty acid biosynthesis (acetyl CoA carboxylase, fatty acid synthase, stearoyl CoA desaturase-1).
The mechanism by which sterols control the proteolytic release of SREBPs from cell membranes is being elucidated through studies of cultured animal cells. The in vivo role of the SREBPs is being studied in transgenic and knockout mice.