期刊
MOLECULAR ENDOCRINOLOGY
卷 21, 期 9, 页码 2099-2111出版社
ENDOCRINE SOC
DOI: 10.1210/me.2007-0002
关键词
-
资金
- NIA NIH HHS [AG10486] Funding Source: Medline
The nuclear receptors pregnane X receptor ( PXR) and constitutive androstane receptor ( CAR) are the primary transcription factors coordinating induced expression of the enzymes and proteins directing oxidative, conjugative, and transport phases of endobiotic and xenobiotic metabolism, whereas hepatocyte nuclear factor 4 alpha ( HNF4 alpha), a regulator of hepatic lipid homeostasis, can modify the PXR/ CAR response. Steroid- and bile acid-sulfotransferase ( SULT2A1) promotes phase II metabolism through its sulfonating action on certain endobiotics,including steroids and bile acids, and on diverse xenobiotics, including therapeutic drugs. This study describes characterization of a PXR- and CAR-inducible composite element in the human SULT2A1 promoter and its synergistic interaction with HNF4 alpha. Inverted and direct repeats of AG( G/ T) TCA ( IR2 and DR4), both binding to PXR and CAR, define the composite element. Differential recognition of the composite element by PXR and CAR is evident because single-site mutation at either IR2 or DR4 in the natural gene abolished the PXR response, whereas mutations at both repeats were necessary to abrogate completely the CAR response. The composite element conferred xenobiotic response to a heterologous promoter, and the cognate ligands induced PXR and CAR recruitment to the chromatin-associated response region. An HNF4 alpha element adjacent to the - 30 position enhanced basal promoter activity. Although functioning as a synergizer, the HNF4 alpha element was not essential for the PXR/ CAR response. An emerging role of SULT2A1 in lipid and caloric homeostasis suggests that illumination on the regulatory interactions driving human SULT2A1 expression may reveal new avenues to control certain metabolic disorders.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据