Proceedings of the National Academy of Sciences of the United States of America

About the PNAS Member Editor
Name Brown, Michael S.
Location The University of Texas Southwestern Medical Center
Primary Field Medical Physiology and Metabolism
 Election Citation
Not available
 Research Interests
My research with my scientific partner, Dr. Joseph Goldstein, 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 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 cells. When cells are replete with sterols, 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). This feedback mechanism assures a steady supply of cholesterol and unsaturated fatty acids, and prevents overaccumulation. Mutant cells with blocks in SREBP processing fail to grow in the absence of added cholesterol and unsaturated fatty acids. Making use of these mutant cell lines, we cloned two membrane-bound proteases and a membrane-bound sterol-sensing regulatory molecule that together mediate the regulated release of SREBPs from membranes. These proteins appear to be key players in the pathway that controls the lipid composition of cell membranes.

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