Hepatocyte nuclear factor 4alpha regulation of bile acid and drug metabolism.
Hepatocyte nuclear factor 4alpha regulation of bile acid and drug metabolism.
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DOI：
10.1517/17425250802707342
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发表时间：
2009-02
影响因子：
4.3
通讯作者：
Chiang JY
中科院分区：
文献类型：
--
作者：
Chiang JY
肝细胞核因子4α（hepatocyte nuclear factor 4α，HNF 4 α）是一种肝脏富集的核受体，在早期形态发生、胎儿肝脏发育、肝脏分化和代谢中起重要作用。人类HNF4α基因突变导致年轻1型糖尿病的成熟发病，这是一种常染色体显性遗传的非胰岛素依赖型糖尿病。HNF 4 α是一种孤儿核受体，其内源性配体尚未被确定。HNF 4 α的反式激活活性通过与辅激活因子相互作用而增强，并被辅抑制因子抑制。最近的研究表明，HNF4α在调节肝脏胆汁酸代谢中起着核心作用。胆汁酸是胆固醇和代谢物的胆汁排泄以及脂肪、营养物质、药物和外源性物质的肠吸收所必需的，以运输和分布到肝脏和其他组织。胆汁酸是激活核受体以控制肝脏和肠道中的脂质和药物代谢的信号分子。因此，HNF4α在胆汁酸和外源性物质代谢的协调调节中起核心作用。特异性激活HNF4α的药物可用于治疗糖尿病、血脂异常和胆汁淤积等代谢性疾病，以及药物代谢和解毒。
The hepatocyte nuclear factor 4α (HNF4α) is a liver-enriched nuclear receptor that plays a critical role in early morphogenesis, fetal liver development, liver differentiation and metabolism. Human HNF4α gene mutations cause maturity on-set diabetes of the young type 1, an autosomal dominant non-insulin-dependent diabetes mellitus. HNF4α is an orphan nuclear receptor because of which the endogenous ligand has not been firmly identified. The trans-activating activity of HNF4α is enhanced by interacting with co-activators and inhibited by corepressors. Recent studies have revealed that HNF4α plays a central role in regulation of bile acid metabolism in the liver. Bile acids are required for biliary excretion of cholesterol and metabolites, and intestinal absorption of fat, nutrients, drug and xenobiotics for transport and distribution to liver and other tissues. Bile acids are signaling molecules that activate nuclear receptors to control lipids and drug metabolism in the liver and intestine. Therefore, HNF4α plays a central role in coordinated regulation of bile acid and xenobiotics metabolism. Drugs that specifically activate HNF4α could be developed for treating metabolic diseases such as diabetes, dyslipidemia and cholestasis, as well as drug metabolism and detoxification.
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