Liver-Enriched Transcription Factors

HNF4的作用？控制胆汁酸的合成和结合。在HNF4的许多有趣的表型中？肝脏缺失的小鼠(HNF4？deltaL)是血清胆汁酸的升高。HNF4？deltaL小鼠血清胆汁酸水平明显高于对照组(HNF4？F/F)。由于胆汁酸是由肝脏中的胆固醇产生的，参与胆汁酸生物合成的许多酶在肝脏中优先表达，因此HNF4？在BA生产中进行了检测。这部分是由于HNF4-deltaL小鼠的基因表达下调所致。在HNF4-deltaL小鼠中，只有在暗周期中，CYP7A1的基因和蛋白表达下降，而在光周期中，HNF4-deltaL小鼠和HNF4？F/F小鼠之间的表达没有差异。无论是光周期还是暗周期，细胞色素P8B1mRNA和酶活性均降低。HNF4？在小鼠Cyp8b1启动子中发现了能够引导HNF4依赖转录的结合位点。令人惊讶的是，由于CYP8B1活性而产生的胆酸衍生的bas，仍然在这些小鼠的血清和胆囊中观察到。这些研究表明，HNF4？HNF4？deltaL小鼠还表现出超长链酰辅酶A合成酶相关基因(VLACSR)和胆汁酸辅酶A连接酶(BAT)的表达降低。这与HNF4？deltaL小鼠的胆汁中未结合胆汁酸和甘氨酸结合胆汁酸水平显著升高有关。与体内的发现一致，HNF4？还发现能直接与小鼠VLACSR和BAT基因启动子结合，并且启动子的活性依赖于HNF4结合部位和HNF4？通过直接调节VLACSR和BAT在体内的表达。这些研究表明HNF4？在胆汁酸合成和结合中起核心作用，并解释了HNF4？deltaL小鼠胆汁酸代谢异常的原因。其他一些基因受HNF4控制？在HNF4？deltaL小鼠中，它们的下调揭示了这一点。这些基因包括编码凝血因子FXII和FXIIIB的基因，UDP-葡萄糖醛酸基转移酶1A9，以及脯氨酸氧化酶，尿苷磷酸化酶。这些基因也被证明具有功能性的HNF4？系紧领带。在胰腺？-细胞，HNF4？被证明影响K(ATP)通道活性的表达，从而部分解释了它与青年1型糖尿病(MODY1)的关系。

Role of HNF4? in control of bile acid synthesis and conjugation. Among the many interesting phenotypes in the HNF4? liver null mice (HNF4?deltaL) is an elevation in serum bile acids. HNF4?deltaL mice have markedly increased levels of serum bile acids (BAs) compared with control floxed mice (HNF4?F/F). Because bile acids are produced from cholesterol in liver and many enzymes involved in their biosynthesis are preferentially expressed in liver, the role of HNF4? in BA production was examined. This is due in part to the downregulation of genes encoding oxysterol 7?-hydroxylase (CYP7A1), sterol 12?-hydroxylase (CYP8B1), and sterol carrier protein x. CYP7A1 mRNA and protein were diminished only during the dark cycle in HNF4?deltaL mice, whereas expression in the light cycle was not different between HNF4?deltaL and HNF4?F/F mice. CYP8B1 mRNA and enzyme activity was reduced regardless of light or dark cycle. An HNF4? binding site was found in the mouse Cyp8b1 promoter that was able to direct HNF4?-dependent transcription. Surprisingly, cholic acid-derived BAs, produced as a result of CYP8B1 activity, were still observed in the serum and gallbladder of these mice. These studies reveal that HNF4? plays a central role in BA homeostasis by regulation of genes involved in BA biosynthesis, including hydroxylation and side chain ?-oxidation of cholesterol in vivo.HNF4?deltaL mice also exhibited decreased expression of the very long chain acyl-CoA synthase-related gene (VLACSR), also called bile acid-CoA ligase, and bile acid-CoA:amino acid N-acyltransferase (BAT). This was associated with markedly elevated levels of unconjugated and glycine-conjugated bile acids in gallbladder of the HNF4?deltaL mice. In agreement with this in vivo finding, HNF4? was also found to bind directly to the mouse VLACSR and BAT gene promoters, and the promoter activities were dependent on HNF4?-binding sites and HNF4? expression by direct regulation of VLACSR and BAT in vivo. These studies indicate HNF4? plays a central role in bile acid synthesis and conjugation and explain why the HNF4?deltaL mice have abnormal bile acid homeostasis.Other genes controlled by HNF4?. A number of other genes are controlled by HNF4? as revealed by their down-regulation in HNF4?deltaL mice. These include the genes encoding blood coagulation factors FXII and FXIIIB, UDP-glucuronosyltransferase 1A9, and proline oxidase, uridine phosphorylase. These genes were also shown to have functional HNF4? binding sties. In the pancreatic ?-cells, HNF4? was shown to influence the expression of the K(ATP) channel activity thus explaining in part its association with maturity onset diabetes of the young, type 1 (MODY1).