Peroxisome proliferator-activated receptor α induces hepatic expression of the human bile acid glucuronidating UDP-glucuronosyltransferase 2B4 enzyme
Peroxisome proliferator-activated receptor α induces hepatic expression of the human bile acid glucuronidating UDP-glucuronosyltransferase 2B4 enzyme
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DOI：
10.1074/jbc.m305361200
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发表时间：
2003-08-29
影响因子：
4.8
通讯作者：
Staels, B
中科院分区：
文献类型：
--
作者：
Barbier, O;Duran-Sandoval, D;Staels, B
葡萄糖醛酸化是多种内源性物质和外源性物质的主要代谢途径，由属于UDP-葡萄糖醛酸基转移酶（UGT）家族的酶催化。在UGT酶中，UGT 2B 4结合多种内源性和外源性分子，被认为是人肝脏中主要的胆汁酸结合UGT酶。在本研究中，我们确定UGT 2B 4作为核受体过氧化物酶体增殖物激活受体α（PPARalpha）的一个新的靶基因，该基因介导贝特类的降血脂作用。将人肝细胞或肝母细胞瘤HepG 2和Huh 7细胞与合成的PPARalpha激动剂、非诺贝酸或Wy 14643孵育，导致UGT 2B 4 mRNA水平升高。此外，用Wy 14643处理HepG 2细胞诱导猪去氧胆酸（一种特异性胆汁酸UGT 2B 4底物）的葡萄糖醛酸化。在PPARalpha野生型和无效小鼠中的UGT 2B mRNA和蛋白质水平的分析显示，PPARalpha也调节啮齿动物中这些酶的基础和纤维素诱导的表达。最后，通过定点诱变和电迁移率变化测定在UGT 2B 4启动子中鉴定了一个PPAR应答元件。这些结果表明，PPARalpha激动剂可以控制细胞毒性胆汁酸的催化作用，并加强了最近的数据，表明PPARalpha在很大程度上参与了脂质和胆固醇代谢的控制，也是人肝细胞中内源性和外源性物质代谢的重要调节剂。
Glucuronidation, a major metabolic pathway for a large variety of endobiotics and xenobiotics, is catalyzed by enzymes belonging to the UDP-glucuronosyl-transferase (UGT) family. Among UGT enzymes, UGT2B4 conjugates a large variety of endogenous and exogenous molecules and is considered to be the major bile acid conjugating UGT enzyme in human liver. In the present study, we identify UGT2B4 as a novel target gene of the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha), which mediates the hypolipidemic action of fibrates. Incubation of human hepatocytes or hepatoblastoma HepG2 and Huh7 cells with synthetic PPARalpha agonists, fenofibric acid, or Wy 14643 resulted in an increase of UGT2B4 mRNA levels. Furthermore, treatment of HepG2 cells with Wy 14643 induced the glucuronidation of hyodeoxycholic acid, a specific bile acid UGT2B4 substrate. Analysis of UGT2B mRNA and protein levels in PPARalpha wild type and null mice revealed that PPARalpha regulates both basal and fibrate-induced expression of these enzymes in rodents also. Finally, a PPAR response element was identified in the UGT2B4 promoter by site-directed mutagenesis and electromobility shift assays. These results demonstrate that PPARalpha agonists may control the catabolism of cytotoxic bile acids and reinforce recent data indicating that PPARalpha, which has been largely implicated in the control of lipid and cholesterol metabolism, is also an important modulator of the metabolism of endobiotics and xenobiotics in human hepatocytes.