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).
This feedback mechanism assures a steady supply of cholesterol and unsaturated fatty acids, and it 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 cells lines, we recently 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 the key players in the pathway that controls the lipid composition of cell membranes.
For a detailed discussion of our reseach, please see the Brown Goldstein Laboratory webpage by clicking on the link above.
RESEARCH INTERESTS
Regulation of cholesterol metabolism and membrane composition
Genetics of human disease
Mechanism of vesicular transport in animal cells
RECENT PUBLICATIONS
Radhakrishnan, A., Goldstein, J.L., McDonald, J.G., and Brown, M.S., "Switch-like Control of SREBP-2 Transport Triggered by Small Changes in ER Cholesterol: A Delicate Balance." Cell Metab., 8:512-521, 2008
Infante, R.E., Wang, M.L., Radhakrishnan, A., Kwon, H.J., Brown, M.S. and Goldstein, J.L., "NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes." Proc. Natl. Acad. Sci. USA, 105:15287-15292, 2008
Brown, M.S. and Goldstein, J.L., "Cholesterol feedback: from Schoenheimer’s bottle to Scap’s MELADL." J. Lipid. Res., S15-S27, 2009
Goldstein, J.L. and Brown, M.S., "History of discovery: The LDL receptor." Arterioscler. Thromb. Vasc. Biol., 29:431-438, 2009
Kwon, H.J., Abi-Mosleh, L., Wang, M.L., Deisenhofer, J., Goldstein, J.L., Brown, M.S., and Infante, R.E., "Structure of N-terminal domain of NPC1 reveals distinct subdomains for binding and transfer of cholesterol." Cell, 137:1213-1224, 2009
SIGNIFICANT PUBLICATIONS
Brown, M.S., and Goldstein, J.L., "A receptor-mediated pathway for cholesterol homeostasis." Science, 232:34-47, April 1986
Reiss, Y., Goldstein, J.L., Seabra, M.C., Casey, P.J., and Brown, M.S., "Inhibition of purified p21ras farnesyl: Protein transferase by Cys-AAX tetrapeptides." Cell, 62:81-88, 1990
Brown, M.S. and Goldstein, J.L., "The SREBP pathway: Regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor." Cell, 89:331-340, May 1997
Brown, M.S., Ye, J., Rawson, R.B., and Goldstein, J.L., "Regulated intramembrane proteolysis: A control mechanism conserved from bacteria to humans." Cell, 100:391-398, 2000
Goldstein, J.L., DeBose-Boyd, R.A. and Brown, M.S., "Protein sensors for membrane sterols." Cell, 124:35-46, 2006
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