Hepatocyte Nuclear Factor 4α (Nuclear Receptor 2A1) Is Essential for Maintenance of Hepatic Gene Expression and Lipid Homeostasis

Abstract

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␣ [HNF1␣], -1␤, -3␣, -3␤, -3␥, -4␣, and -6 and members of the c/ebp family). Of these, only HNF4␣ (nuclear receptor 2A1) and HNF1␣ appear to be correlated with the differentiated phenotype of cultured hepatoma cells. HNF1␣-null mice are viable, indicating that this factor is not an absolute requirement for the formation of an active hepatic parenchyma. In contrast, HNF4␣-null mice die during embryogenesis. Moreover, recent in vitro experiments using tetraploid aggregation suggest that HNF4␣ is indispensable for hepatocyte differentiation. However, the function of HNF4␣ in the maintenance of hepatocyte differentiation and function is less well understood. To address the function of HNF4␣ in the mature hepatocyte, a conditional gene knockout was produced using the Cre-loxP system. Mice lacking hepatic HNF4␣ 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␣ is central to the maintenance of hepatocyte differentiation and is a major in vivo regulator of genes involved in the control of lipid homeostasis.The adult liver executes numerous functions that are essential for metabolic homeostasis including plasma protein synthesis; carbohydrate, lipid, and amino acid metabolism; and xenobiotic metabolism. The majority of these functions are performed by hepatocytes. Hepatocyte-enriched transcription factors control transcription of genes that are preferentially expressed in liver (5). Our understanding of the role of liverenriched transcription factors in gene expression has largely been developed using transfection assays in cultured cells. Cisacting elements for transcription factor binding have been characterized using this approach in conjunction with in vitro DNA binding assays. However, many genes have regulatory elements for several transcription factors, and it becomes difficult to assess which factor predominates in vivo. Moreover, it is becoming increasingly clear that the in vitro regulation of a gene is not always reflected by the in vivo situation. For example, numerous hepatic genes are transactivated by hepatocyte nuclear factor 3␤ (HNF3␤) in vitro but deletion of HNF3␤ in the mature hepatocyte using ...

Intermittent calorie restriction largely counteracts the adverse health effects of a moderate‐fat diet in aging C57BL/6J mice

“…Furthermore, IPA upstream regulator analysis suggested that the factors driving the differential gene expression between the INT and MF diet were TGFB1 and a number other cytokines including TNF, IL4, and IFNγ. On the contrary, differential gene expression between INT and CR‐ exposed mice was due to NFE2L2 (or NRF2) activity well‐known for its antioxidant response 52, XBP1, acknowledged to mediate ER stress/apoptosis 53, 54, and the well‐established liver the liver transcription factor HNF4A 55. Remarkably, our data do not point toward the involvement of one or more of the four well‐established pathways involved in mediating the CR effect including (1) the insulin like growth factor (IGF‐1)/insulin signaling pathway, (2) the sirtuin pathway, (3) the adenosine monophosphate activated protein kinase pathway, and (4) the target of rapamycin pathway 6, 56, as upstream regulators.…”

Regulation of gene transcription by fatty acids

“…As conventional gene knock-out is lethal, Hayhurst et al (2001) addressed the role of HNF4a in mature hepatocytes using a conditional gene knockout. Mice lacking hepatic HNF-4a exhibit major perturbations of lipid metabolism with increased accumulation of lipid in the liver and reduced plasma cholesterol and triacylglycerol concentrations.…”

Signalling cross-talk between hepatocyte nuclear factor 4α and growth-hormone-activated STAT5b

“…HNF4α (hepatocyte nuclear factor 4α) is a liver-enriched member of the nuclear receptor superfamily that regulates the expression of genes involved in fatty acid, cholesterol and glucose metabolism, apolipoprotein synthesis and liver development [1][2][3]. HNF4α regulates the expression of genes in liver, both directly and indirectly, through interaction with other HNFs, including the variant homeodomain protein HNF1α, C/EBPs (CCAAT/enhancerbinding proteins), HNF3 winged helix factors and the one-cut homeoprotein, HNF6 [4].…”

“…Among the HNFs, HNF4α is proposed to play a central role in the regulation of liver-enriched transcription factors and their liver-specific targets, including liver CYP (cytochrome P450) genes [5]. The key regulatory role of HNF4α was demonstrated in a liver-HNF4α-deficient mouse model [2], in which HNF4α was shown to control the expression of HNFs in vivo in both a positive manner (HNF1α, C/EBPα and C/EBPβ) and a negative manner {HNF3α, HNF3β, HNF6 and the HNF4α coactivator, PGC-1α [PPARγ (peroxisome-proliferator-activated receptor γ ) co-activator-1 α]} [6].…”