Liver-Enriched Transcription Factors

HNF4的作用？控制胆汁酸的合成和缀合。在许多有趣的表型中，HNF4？肝缺失小鼠(HNF4？deltaL)是血清胆汁酸的升高。HNF4吗?与对照组相比，deltaL小鼠血清胆汁酸（BAs）水平显著升高（HNF4 /F）。由于胆汁酸是由肝脏中的胆固醇产生的，并且参与胆汁酸生物合成的许多酶优先在肝脏中表达，因此HNF4？在BA生产中的应用这在一定程度上是由于编码氧甾醇7？-羟化酶（CYP7A1），甾醇12？-羟化酶（CYP8B1）和甾醇载体蛋白x。CYP7A1 mRNA和蛋白仅在HNF4？而在光照周期中，HNF4？deltaL和HNF4？/ F老鼠。无论光照周期还是黑暗周期，CYP8B1 mRNA和酶活性均降低。一个HNF4吗?在小鼠Cyp8b1启动子中发现了能够指导HNF4？端依赖转录。令人惊讶的是，在这些小鼠的血清和胆囊中仍然观察到由CYP8B1活性产生的胆酸衍生的BAs。这些研究表明，HNF4？通过调控参与BA生物合成的基因，包括羟基化和侧链？-体内胆固醇氧化。hnf4 ？deltaL小鼠也表现出极长链酰基辅酶a合成酶相关基因（VLACSR）的表达减少，也称为胆汁酸-辅酶a连接酶和胆汁酸-辅酶a：氨基酸n -酰基转移酶（BAT）。这与HNF4患者胆囊中未结合胆汁酸和甘氨酸结合胆汁酸水平显著升高有关。deltaL老鼠。与这一体内发现一致，HNF4？还发现直接结合小鼠VLACSR和BAT基因启动子，启动子活性依赖于HNF4？-结合位点和HNF4？直接调控VLACSR和BAT在体内的表达。这些研究表明，HNF4？在胆汁酸的合成和结合中起核心作用，并解释为什么HNF4？deltaL小鼠胆汁酸稳态异常。其他受HNF4控制的基因。其他一些基因是由HNF4控制的。它们在HNF4？deltaL老鼠。这些基因包括编码凝血因子FXII和FXIIIB、udp -葡萄糖醛基转移酶1A9和脯氨酸氧化酶、尿苷磷酸化酶的基因。这些基因也被证明具有功能性的HNF4？绑定风格。在胰腺？肽,HNF4 ?影响K（ATP）通道活性的表达，从而部分解释了其与年轻人1型糖尿病（MODY1）成熟发病的关联。

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).