The Brown/Goldstein laboratory is unique in medical research because it has been supervised jointly by two scientists for 33 years. The laboratory is devoted to solving a fundamental problem: how do animals regulate the synthesis of cholesterol and other lipids so as to maintain constant membrane composition? Several years ago we discovered sterol regulatory element-binding proteins (SREBPs), membrane-bound transcription factors that activate genes encoding more than 30 enzymes required for lipid synthesis, uptake and storage. To reach the nucleus the SREBPs must travel to the Golgi complex where proteases release the active transcription domains. We call this the SREBP pathway. Excess cholesterol blocks SREBP movement, thus inhibiting lipid synthesis and establishing a feedback loop. Defects in SREBP regulation contribute to common diseases, ranging from heart attacks to obesity and diabetes.
RESEARCH INTERESTS
Cholesterol and Lipoprotein Metabolism
Genetics of Human Disease
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
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
Guan, H.-P., Goldstein, J.L., M.S. Brown, and Liang, G., "Accelerated fatty acid oxidation in muscle averts fasting-induced hepatic steatosis in SJL/J mice." J. Biol. Chem., 284:24644-24652, 2009
SIGNIFICANT PUBLICATIONS
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, 1997
Shimomura, I., Hammer, R.E., Ikemoto, S., Brown, M.S., and Goldstein, J.L., "Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy." Nature, 401:73-76, 1999
Yang, T., Espenshade, P.J., Wright, M.E., Yabe, D., Gong, Y., Aebersold, R., Goldstein, J.L., and Brown, M.S., "Crucial step in cholesterol homeostasis: Sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in the ER." Cell, 110:489-500, 2002
Radhakrishnan, A., Sun, L.-P., Kwon, H.J., Brown, M.S., and Goldstein, J.L., "Direct binding of cholesterol to the purified membrane region of SCAP: Mechanism for a sterol-sensing domain." Molecular Cell, 15:259-268, 2004
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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