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
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
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DOI：
10.1124/jpet.109.153510
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发表时间：
2009-10-01
影响因子：
3.5
通讯作者：
Li, Song
中科院分区：
文献类型：
--
作者：
Li, Jiang;Wilson, Annette;Li, Song
不对称二甲基精氨酸（ADMA）是内皮型一氧化氮合酶（eNOS）的内源性抑制剂，血浆中ADMA浓度升高被认为是多种心血管疾病的危险因素。循环ADMA主要通过阳离子氨基酸（CAT）家族的系统Y（+）载体被肝脏和肾脏摄取，随后被二甲基精氨酸二甲氨基水解酶（DDAH）代谢。因此，靶向增强ADMA代谢的药剂可证明可用于预防和/或治疗各种类型的心血管疾病。法尼醇X受体（FXR）是核受体超家族成员，在维持胆固醇和胆汁酸稳态中起重要作用。我们在此报道，用FXR激动剂3-（2，6-二氯苯基）-4-（3 '-羧基-2-氯芪-4-基）氧甲基-5-异丙基异恶唑（GW 4064）治疗小鼠导致肝脏和肾脏中DDAH-1和CAT-1的表达增加。在培养的人肝细胞和肾近端肾小管上皮细胞中，GW 4064增加CAT-1表达，这与ADMA的细胞摄取显著增加有关。启动子分析表明，CAT-1基因可能是FXR的作用靶基因，CAT-1基因启动子区存在功能性FXR反应元件。这些数据表明，FXR可能通过协调调节肝脏和肾脏中的DDAH-1和CAT-1，在调节血液中ADMA水平中发挥重要作用。
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.