The major goals of our research have been to identify the mechanisms of activation of the farnesoid X receptor (FXR) and to define its role in regulating metabolic pathways. To this end, we have identified four human and murine FXR transcripts derived from a single gene that encode four different protein isoforms. Our identification of a four amino acid motif (MYTG), located immediately adjacent to the DNA binding domain of two of the four isoforms, dramatically altered our thinking about this transcription factor; new and exciting data suggest that the presence of this motif affects transactivation of certain hepatic and adrenal genes. We have recently discovered that activated FXR has a pronounced effect on glucose metabolism in mice and is highly protective against the acute hepatoxicity produced by toxic xenobiotics and from the toxic effects of IPS (lipopolysaccharide). We have also recently obtained evidence that FXR regulates a number of steroidogenic genes, suggesting a functional role for FXR in the adrenal cortex. Based on these data, generated during the current grant period, we propose to conduct mechanistic studies to elucidate the roles of FXR in i) the control of plasma glucose levels and hepatic glucose metabolism, ii) the control of plasma and hepatic lipid levels, iii) protection of the liver from damage induced by xenobiotics such as acetaminophen, iv) protecting mice from endotoxin shock and bacterial infection and v) the regulation of target genes in adrenal steroidogenic cells. These studies will be aided by the availability of FXR transgenic and FXR-/- mice, and mice lacking FXR in the liver or intestine, and adenovirus expressing individual FXR isoforms. To complement these approaches, mechanistic studies will be conducted to elucidate the function of the MYTG motif present in two of the four FXR isoforms. Taken together, these studies will identify novel regulatory mechanisms by which FXR isoforms activate transcription. In addition, these studies will elucidate the role of FXR in glucose, steroid and drug metabolism and in resistance to endotoxin.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068445-06
Application #
7101101
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Wassef, Momtaz K
Project Start
2001-09-01
Project End
2010-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
6
Fiscal Year
2006
Total Cost
$377,173
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
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
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
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
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
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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