PT - JOURNAL ARTICLE AU - Jiang Li AU - Annette Wilson AU - Xiang Gao AU - Ramalinga Kuruba AU - Youhua Liu AU - Samuel Poloyac AU - Bruce Pitt AU - Wen Xie AU - Song Li TI - Coordinated Regulation of Dimethylarginine Dimethylaminohydrolase-1 and Cationic Amino Acid Transporter-1 by Farnesoid X Receptor in Mouse Liver and Kidney and Its Implication in the Control of Blood Levels of Asymmetric Dimethylarginine AID - 10.1124/jpet.109.153510 DP - 2009 Oct 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 234--243 VI - 331 IP - 1 4099 - http://jpet.aspetjournals.org/content/331/1/234.short 4100 - http://jpet.aspetjournals.org/content/331/1/234.full SO - J Pharmacol Exp Ther2009 Oct 01; 331 AB - Asymmetric dimethylarginine (ADMA) is a potent endogenous inhibitor of endothelial nitric-oxide synthase (eNOS), and increased plasma concentrations of ADMA have been regarded as a risk factor for a number of cardiovascular diseases. Circulating ADMA is largely taken up by liver and kidney via system y+ carriers of the cationic amino acid (CAT) family and subsequently metabolized by dimethylarginine dimethylaminohydrolases (DDAHs). As such, agents targeted at enhancing ADMA metabolism may prove to be useful in the prevention and/or treatment of various types of cardiovascular disease. Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily and plays an important role in the maintenance of cholesterol and bile acid homeostasis. We report here that treatment of mice with an FXR agonist 3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole; GW4064) led to increased expression of DDAH-1 and CAT-1 in both liver and kidney. In cultured human hepatocytes and kidney proximal tubular epithelial cells, GW4064 increased CAT-1 expression, and this was associated with a significant increase in the cellular uptake of ADMA. Promoter analyses suggest that CAT-1 is a likely target of FXR, and a functional FXR response element was found in the promoter region of CAT-1 gene. These data suggest that FXR may play an important role in regulating blood levels of ADMA via coordinated regulation of DDAH-1 and CAT-1 in liver and kidney. © 2009 by The American Society for Pharmacology and Experimental Therapeutics