Chenodeoxycholic acid (CDCA), a primary bile acid, has recently been shown to activate the farnesoid X receptor (FXR), a member of the nuclear hormone receptor superfamily. Recent data suggest that activated FXR controls both bile acid biosynthesis and plasma lipid levels. As such, FXR may affect the development of gallstones and/or atherosclerosis. However at the current time, very little is known about the target genes and metabolic pathways that are affected by activated FXR. In the first specific aim, we propose to use Suppression Subtractive Hybridization and DNA microarrays to identify genes that are regulated by CDCA-activated FXR. These studies will utilize HepG2 and Caco2 cells that stably overexpress high levels of FXR in order to more easily identify FXR-target genes. We will use normal, FXR-/- or VP16-FXR transgenic mice, treated with FXR ligands, to demonstrate (i) that these same genes are induced in vivo and (ii) that activation of FXR results in a decrease in plasma lipids. In the second specific aim, we will identify FXREs and other critical cis elements in the promoters of a few selected genes that have been identified in aim 1, so as to confirm that these genes are direct targets of FXR/CDCA. In the third aim, we will generate mice that overexpress rat VP16-FXR in their livers (see aim 1). Finally, in specific aim 4, we will isolate cell lines derived from HepG2 and Caco2 cells that express either FXR1, FXR2, or FXR3. The induction of target genes, identified in aim 1, by each FXR isoform will be determined in order to test the hypothesis that specific genes/metabolic pathways are activated by each FXR isoforms.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068445-04
Application #
6780383
Study Section
Special Emphasis Panel (ZRG1-SSS-T (01))
Program Officer
Wassef, Momtaz K
Project Start
2001-09-01
Project End
2005-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
4
Fiscal Year
2004
Total Cost
$344,250
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
de Aguiar Vallim, Thomas Q; Tarling, Elizabeth J; Kim, Tammy et al. (2013) MicroRNA-144 regulates hepatic ATP binding cassette transporter A1 and plasma high-density lipoprotein after activation of the nuclear receptor farnesoid X receptor. Circ Res 112:1602-12
Zhang, Yanqiao; Ge, Xuemei; Heemstra, Lydia A et al. (2012) Loss of FXR protects against diet-induced obesity and accelerates liver carcinogenesis in ob/ob mice. Mol Endocrinol 26:272-80
Yin, Liya; Ma, Huiyan; Ge, Xuemei et al. (2011) Hepatic hepatocyte nuclear factor 4? is essential for maintaining triglyceride and cholesterol homeostasis. Arterioscler Thromb Vasc Biol 31:328-36
Tarling, Elizabeth J; Edwards, Peter A (2011) ATP binding cassette transporter G1 (ABCG1) is an intracellular sterol transporter. Proc Natl Acad Sci U S A 108:19719-24
Lee, Florence Ying; de Aguiar Vallim, Thomas Quad; Chong, Hansook Kim et al. (2010) Activation of the farnesoid X receptor provides protection against acetaminophen-induced hepatic toxicity. Mol Endocrinol 24:1626-36
Tarling, Elizabeth J; Bojanic, Dragana D; Tangirala, Rajendra K et al. (2010) Impaired development of atherosclerosis in Abcg1-/- Apoe-/- mice: identification of specific oxysterols that both accumulate in Abcg1-/- Apoe-/- tissues and induce apoptosis. Arterioscler Thromb Vasc Biol 30:1174-80
Chong, Hansook Kim; Infante, Aniello M; Seo, Young-Kyo et al. (2010) Genome-wide interrogation of hepatic FXR reveals an asymmetric IR-1 motif and synergy with LRH-1. Nucleic Acids Res 38:6007-17
Zhang, Yanqiao; Yin, Liya; Anderson, Jody et al. (2010) Identification of novel pathways that control farnesoid X receptor-mediated hypocholesterolemia. J Biol Chem 285:3035-43
Tarr, Paul T; Tarling, Elizabeth J; Bojanic, Dragana D et al. (2009) Emerging new paradigms for ABCG transporters. Biochim Biophys Acta 1791:584-93
Zhang, Yanqiao; Edwards, Peter A (2008) FXR signaling in metabolic disease. FEBS Lett 582:10-8

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