Nuclear hormone receptors comprise a large family of ligand-activated transcription factors. The physiologic ligands that bind and activate these receptors are generally small lipophilic molecules that are often derived from dietary sources. Recent studies indicate that a subset of nuclear hormone receptors serve as lipid sensors that can coordinately regulate the expression of genes controlling the intracellular levels of their lipid ligands (Chawla, et al. 2000). For example the oxysterol receptors, LXRa and LXRb, regulate the expression of proteins that promote catabolism (cholesterol 7a hydroxylase), efflux (ATP-binding cassette transporters ABCA1, ABCG5 and ABCG8) and HDL-mediated reverse transport (apoE, PLTP, CETP) of cholesterol. In a similar manner, the bile acid receptor FXR and the xenobiotic receptors PXR and CAR, regulate ABC transporters that affect the cellular concentrations of their respective lipid ligands.
These early studies focused on the role of these receptors in liver and intestine. However, many of these lipid-sensing receptors are also highly expressed in the endocrine pancreas and brain. Therefore current research in the Repa lab is aimed at elucidating the roles of ophan nuclear receptors in these tissues, and suggests that these important transcription factors can impact the progression of such diseases as diabetes, Alzheimer’s and other neurodegenerative disorders.
RESEARCH INTERESTS
Diabetes
Nuclear hormone receptor
LXR, FXR, PXR, beta-cell, islet
Bile acids, Cholesterol
Transcription
RECENT PUBLICATIONS
Repa, J. J., H. Li, T. C. Frank-Cannon, M. A. Valasek, S. D. Turldy, M. G. Tansey, and J. M. Dietschy, "Liver X receptor activation enhances cholesterol loss from the brain, decreases neuroinflammation, and increases survival of the NPC1 mouse." J. Neurosci., 27:14470-14480, December 2007
Valasek MA, Repa JJ, Quan G, Dietschy JM, Turley SD, "Inhibiting intestinal NPC1L1 activity prevents diet-induced increase in biliary cholesterol in Golden Syrian hamsters." Am J Physiol Gastrointest Liver Physiol, 295(4):G813-22, October 2008
Chuang JC, Cha JY, Garmey JC, Mirmira RG, Repa JJ, "Research resource: nuclear hormone receptor expression in the endocrine pancreas." Mol Endocrinol, 22(10):2353-63, October 2008
Sakiyama H, Wynn RM, Lee WR, Fukasawa M, Mizuguchi H, Gardner KH, Repa JJ, Uyeda K, "Regulation of nuclear import/export of carbohydrate response element-binding protein (ChREBP): interaction of an alpha-helix of ChREBP with the 14-3-3 proteins and regulation by phosphorylation." J Biol Chem, 283(36):24899-908, September 2008
Li H, Turley SD, Liu B, Repa JJ, Dietschy JM, "GM2/GD2 and GM3 gangliosides have no effect on cellular cholesterol pools or turnover in normal or NPC1 mice." J Lipid Res, 49(8):1816-28, August 2008
SIGNIFICANT PUBLICATIONS
Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, Shimomura I, Shan B, Brown MS, Goldstein JL, Mangelsdorf DJ, "Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta." Genes Dev, 14(22):2819-30, November 2000
Repa JJ, Lund EG, Horton JD, Leitersdorf E, Russell DW, Dietschy JM, Turley SD, "Disruption of the sterol 27-hydroxylase gene in mice results in hepatomegaly and hypertriglyceridemia. Reversal by cholic acid feeding." J Biol Chem, 275(50):39685-92., December 2000
Zhang Y, Repa JJ, Gauthier K, Mangelsdorf DJ, "Regulation of lipoprotein lipase by the oxysterol receptors, LXRalpha and LXRbeta." J Biol Chem, 276(46):43018-24, November 2001
Laffitte BA, Repa JJ, Joseph SB, Wilpitz DC, Kast HR, Mangelsdorf DJ, Tontonoz P, "LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes." Proc Natl Acad Sci U S A, 98(2):507-12, January 2001
Repa JJ, Turley SD, Lobaccaro JA, Medina J, Li L, Lustig K, Shan B, Heyman RA, Dietschy JM, Mangelsdorf DJ, "Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers." Science, 289(5484):1524-9, September 2000
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