Michael S. Brown

The University of Texas Southwestern Medical Center

Election Year: 1980
Primary Section: 42, Medical Physiology and Metabolism
Membership Type: Member
Photo Credit: David Gresham


Michael S. Brown received an M.D. degree in 1966 from the University of Pennsylvania. He was an intern and resident at the Massachusetts General Hospital, and a post doctoral fellow with Earl Stadtman at the National Institutes of Health. He is currently Paul J. Thomas Professor of Molecular Genetics and Director of the Jonsson Center for Molecular Genetics at the University of Texas Southwestern Medical School in Dallas. Dr. Brown and his colleague, Dr. Joseph L. Goldstein, discovered the low density lipoprotein (LDL) receptor, which controls cholesterol in blood and in cells. They showed that mutations in this receptor cause Familial Hypercholesterolemia, a disorder that leads to premature heart attacks. Their work laid the groundwork for drugs called statins that block cholesterol synthesis, increase LDL receptors, lower blood cholesterol and prevent heart attacks. Statins are taken daily by more than 20 million people worldwide. Brown and Goldstein shared many awards for this work, including the U.S. National Medal of Science and the Nobel Prize for Medicine or Physiology. Dr. Brown served for 16 years on the Board of Directors of Pfizer, and he is currently a Director of Regeneron Pharmaceuticals.

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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