Hepatocyte nuclear factor 4α (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis
Hepatocyte nuclear factor 4α (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis
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DOI：
10.1128/mcb.21.4.1393-1403.2001
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发表时间：
2001-02-01
影响因子：
5.3
通讯作者：
Gonzalez, FJ
中科院分区：
文献类型：
--
作者：
Hayhurst, GP;Lee, YH;Gonzalez, FJ
肝脏的众多功能主要在转录水平上由少数几种肝细胞富集转录因子（肝细胞核因子1α[HNF1α]、 -1β、 -3α、 -3β、 -3γ、4α和 -6以及C/EBP家族成员）的协同作用所控制。在这些因子中，似乎只有HNF4α（核受体2A1）和HNF1α与培养的肝癌细胞的分化表型相关。HNF1α基因缺失的小鼠能够存活，这表明该因子对于活性肝实质的形成并非绝对必需。相比之下，HNF4α基因缺失的小鼠在胚胎发育期间死亡。此外，最近利用四倍体聚合法进行的体外实验表明，HNF4α对于肝细胞分化是必不可少的。然而，HNF4α在维持肝细胞分化和功能方面的作用还不太清楚。为了研究HNF4α在成熟肝细胞中的功能，利用Cre - loxP系统构建了条件性基因敲除小鼠。肝脏中缺乏HNF4α表达的小鼠肝脏中脂质蓄积，血清胆固醇和甘油三酯水平大幅降低，血清胆汁酸浓度升高。观察到的表型可以通过以下原因解释：（i）由于编码载脂蛋白B和微粒体甘油三酯转移蛋白的基因表达降低，极低密度脂蛋白分泌选择性中断；（ii）由于主要的高密度脂蛋白受体——清道夫受体BI的表达增加，肝脏对胆固醇的摄取增加；（iii）由于主要的基底外侧胆汁酸转运蛋白——牛磺胆酸钠协同转运蛋白和有机阴离子转运蛋白1的下调，肝脏对胆汁酸的摄取减少。这些数据表明，HNF4α对于维持肝细胞分化至关重要，并且是体内参与脂质稳态调控的基因的主要调节因子。
The numerous functions of the liver are controlled primarily at the transcriptional level by the concerted actions of a limited number of hepatocyte-enriched transcription factors (hepatocyte nuclear factor 1 alpha [HNF1 alpha], -1 beta, -3 alpha, -3 beta, -3 gamma, 4 alpha, and -6 and members of the c/ebp family). Of these, only HNF4 alpha (nuclear receptor 2A1) and HNF1 alpha appear to be correlated with the differentiated phenotype of cultured hepatoma cells. HNF1 alpha -null mice are viable, indicating that this factor is not an absolute requirement for the formation of an active hepatic parenchyma. In contrast, HNF4 alpha -null mice die during embryogenesis. Moreover, recent in vitro experiments using tetraploid aggregation suggest that HNF4 alpha is indispensable for hepatocyte differentiation, However, the function of HNF4 alpha in the maintenance of hepatocyte differentiation and function is less well understood. To address the function of HNF4 alpha in the mature hepatocyte, a conditional gene knockout was produced using the Cre-loxP system. Mice lacking hepatic HNF4 alpha expression accumulated lipid in the liver and exhibited greatly reduced serum cholesterol and triglyceride levels and increased serum bile acid concentrations. The observed phenotypes may be explained by (i) a selective disruption of very-low-density lipoprotein secretion due to decreased expression of genes encoding apolipoprotein B and microsomal triglyceride transfer protein, (ii) an increase in hepatic cholesterol uptake due to increased expression of the major high-density lipoprotein receptor, scavenger receptor BI, and (iii) a decrease in bile acid uptake to the liver due to down-regulation of the major basolateral bile acid transporters sodium taurocholate cotransporter protein and organic anion transporter protein 1. These data indicate that HNF4 alpha is central to the maintenance of hepatocyte differentiation and is a major in vivo regulator of genes involved in the control of lipid homeostasis.