Dietrich Christoph G, Martin Ina V, Porn Anne C, Voigt Sebastian, Gartung Carsten, Trautwein Christian, Geier Andreas
Department of Internal Medicine III, Division of Gastroenterology and Hepatology, University Hospital Aachen, Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.
Am J Physiol Gastrointest Liver Physiol. 2007 Sep;293(3):G585-90. doi: 10.1152/ajpgi.00175.2007. Epub 2007 Jul 19.
Fasting induces numerous adaptive changes in metabolism by several central signaling pathways, the most important represented by the HNF4alpha/PGC-1alpha-pathway. Because HNF4alpha has been identified as central regulator of basolateral bile acid transporters and a previous study reports increased basolateral bile acid uptake into the liver during fasting, we hypothesized that HNF4alpha is involved in fasting-induced bile acid uptake via upregulation of basolateral bile acid transporters. In rats, mRNA of Ntcp, Oatp1, and Oatp2 were significantly increased after 48 h of fasting. Protein expression as determined by Western blot showed significant increases for all three transporters 72 h after the onset of fasting. Whereas binding activity of HNF1alpha in electrophoretic mobility shift assays remained unchanged, HNF4alpha binding activity to the Ntcp promoter was increased significantly. In line with this result, we found significantly increased mRNA expression of HNF4alpha and PGC-1alpha. Functional studies in HepG2 cells revealed an increased endogenous NTCP mRNA expression upon cotransfection with either HNF4alpha, PGC-1alpha, or a combination of both. We conclude that upregulation of the basolateral bile acid transporters Ntcp, Oatp1, and Oatp2 in fasted rats is mediated via the HNF4alpha/PGC-1alpha pathway.
禁食通过几种核心信号通路在代谢方面引发众多适应性变化，其中最重要的是以HNF4α/PGC-1α通路为代表。由于HNF4α已被确定为基底外侧胆汁酸转运蛋白的核心调节因子，且先前的一项研究报道禁食期间肝脏对基底外侧胆汁酸的摄取增加，我们推测HNF4α通过上调基底外侧胆汁酸转运蛋白参与禁食诱导的胆汁酸摄取。在大鼠中，禁食48小时后Ntcp、Oatp1和Oatp2的mRNA显著增加。通过蛋白质印迹法测定的蛋白质表达显示，禁食开始72小时后，所有这三种转运蛋白均显著增加。虽然在电泳迁移率变动分析中HNF1α的结合活性保持不变，但HNF4α与Ntcp启动子的结合活性显著增加。与这一结果一致，我们发现HNF4α和PGC-1α的mRNA表达显著增加。在HepG2细胞中的功能研究表明，与HNF4α、PGC-1α或两者组合共转染后，内源性NTCP mRNA表达增加。我们得出结论，禁食大鼠中基底外侧胆汁酸转运蛋白Ntcp、Oatp1和Oatp2的上调是通过HNF4α/PGC-1α通路介导的。
