scholarly journals Hepatocyte nuclear factor-4alpha mediates the stimulatory effect of peroxisome proliferator-activated receptor gamma co-activator-1alpha (PGC-1alpha) on glucose-6-phosphatase catalytic subunit gene transcription in H4IIE cells

2003 ◽  
Vol 369 (1) ◽  
pp. 17-22 ◽  
Author(s):  
Jared N. BOUSTEAD ◽  
Beth T. STADELMAIER ◽  
Angela M. EEDS ◽  
Peter O. WIEBE ◽  
Christina A. SVITEK ◽  
...  
Keyword(s):  
Fusion Gene ◽  
Catalytic Subunit ◽  
Peroxisome Proliferator ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Peroxisome Proliferator Activated Receptor ◽  
H4iie Cells ◽  
Evolutionarily Conserved ◽  
Hepatocyte Nuclear Factor 4Α ◽  
Hepatocyte Nuclear Factor 4Alpha

It has recently been shown that adenoviral-mediated expression of peroxisome proliferator-activated receptor γ co-activator-1α (PGC-1 α) in hepatocytes stimulates glucose-6-phosphatase catalytic subunit (G6Pase) gene expression. A combination of fusion gene, gel retardation and chromatin immunoprecipitation assays revealed that, in H4IIE cells, PGC-1α mediates this stimulation through an evolutionarily conserved region of the G6Pase promoter that binds hepatocyte nuclear factor-4α.

scholarly journals Modulation of hepatocyte nuclear factor-4α function by the peroxisome-proliferator-activated receptor-γ co-activator-1α in the acute-phase response

2008 ◽  
Vol 415 (2) ◽  
pp. 289-296 ◽  
Author(s):  
Zhongyan Wang ◽  
Peter A. Burke
Keyword(s):  
Dna Binding ◽  
Binding Sites ◽  
Acute Phase Response ◽  
Peroxisome Proliferator ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Binding Ability ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cytokine Treatment ◽  
Hepatocyte Nuclear Factor 4Α

HNF-4α (hepatocyte nuclear factor-4α) is a key regulator of liver-specific gene expression. To understand the mechanisms governing the regulation of HNF-4α function during the APR (acute-phase response), the effects of transcription co-activators, including p300, PGC-1α (peroxisome-proliferator-activated receptor-γ co-activator-1α) and SRC (steroid receptor co-activator)-1α were investigated in an injury cell model. We have shown previously that the HNF-4α-sensitive APR genes ApoB (apolipoprotein B), TTR (transthyretin) and α1-AT (α1-antitrypsin) were regulated at the DNA binding and transcriptional levels after cytokine stimulation. We now show that co-activators have a differential impact on the transactivation of HNF-4α-sensitive genes via HNF-4α-binding sites in ApoB, TTR or α1-AT promoters. PGC-1α strongly enhances the transactivation of ApoB and α1-AT and, to a lesser extent, of TTR, whereas SRC-1α and p300 only have a weak or no effect on these three genes. More importantly, it was found that PGC-1α has a novel role in the modulation of the binding ability of HNF-4α in response to cytokine treatment. Using in vitro and in vivo approaches, electrophoretic mobility-shift and chromatin immunoprecipitation assays, we demonstrate that the reduced HNF-4α–DNA binding ability induced by cytokines is eliminated by overexpression of PGC-1α. Cytokine treatment does not significantly alter the protein levels of HNF-4α and PGC-1α, but it does reduce the recruitment of PGC-1α to HNF-4α-binding sites and thereby decreases transcriptional activity. These results establish the importance of PGC-1α for HNF-4α function and describe a new HNF-4α-dependent regulatory mechanism that is involved in the response to injury.

Abstract 248: Hepatocyte Nuclear Factor 4α Regulates Lipoprotein Metabolism and Atherosclerosis

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Yang Xu ◽  
Munaf Zalzala ◽  
Yuanyuan Li ◽  
Yanqiao Zhang
Keyword(s):  
Critical Role ◽  
Lipoprotein Metabolism ◽  
Clinical Importance ◽  
Nuclear Hormone Receptor ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Lipid Disorder ◽  
Atherosclerotic Lesions ◽  
Hepatocyte Nuclear Factor 4Α ◽  
Hepatocyte Nuclear Factor 4Alpha

Hepatocyte nuclear factor 4alpha (HNF4a) is a nuclear hormone receptor and highly expressed in the liver. Mutations in human HNF4a causes maturity-onset diabetes of the young type 1 (MODY1) and lipid disorder. We investigated the role of loss of hepatic HNF4a in lipid and lipoprotein metabolism using both adenovirus-mediated gene knockdown (Ad-shHNF4a) and liver-specific HNF4a knockout (L-HNF4a-/-) mice. Our data show that loss of hepatic HNF4a caused hypolipidemia and fatty liver disease. Plasma total cholesterol and triglyceride levels were significantly reduced whereas hepatic triglyceride levels were markedly increased. There effects were caused by impaired VLDL secretion. We further determined the effect of loss of hepatic HNF4a in atherosclerosis using ApoE-/- or Ldlr-/- mice. Our data show that loss of hepatic HNF4a caused a marked reduction in the atherosclerotic lesions when mice were challenged with a Western diet. Our data indicate that hepatic HNF4a plays a critical role in modulating lipid and lipoprotein metabolism and the development of atherosclerosis. Since human HNF4a mutations are found in MODY1 patients, this study may be of clinical importance.

scholarly journals Hepatocyte Nuclear Factor 4α Coordinates a Transcription Factor Network Regulating Hepatic Fatty Acid Metabolism

2009 ◽  
Vol 30 (3) ◽  
pp. 565-577 ◽  
Author(s):  
Celia Pilar Martinez-Jimenez ◽  
Irene Kyrmizi ◽  
Philippe Cardot ◽  
Frank J. Gonzalez ◽  
Iannis Talianidis
Keyword(s):  
Transcription Factor ◽  
Fatty Acid ◽  
Target Genes ◽  
Fatty Acid Transport ◽  
Peroxisome Proliferator ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Acid Transport ◽  
Transcription Factor Network ◽  
Hepatocyte Nuclear Factor 4Α

ABSTRACT Adaptation of liver to nutritional signals is regulated by several transcription factors that are modulated by intracellular metabolites. Here, we demonstrate a transcription factor network under the control of hepatocyte nuclear factor 4α (HNF4α) that coordinates the reciprocal expression of fatty acid transport and metabolizing enzymes during fasting and feeding conditions. Hes6 is identified as a novel HNF4α target, which in normally fed animals, together with HNF4α, maintains PPARγ expression at low levels and represses several PPARα-regulated genes. During fasting, Hes6 expression is diminished, and peroxisome proliferator-activated receptor α (PPARα) replaces the HNF4α/Hes6 complex on regulatory regions of target genes to activate transcription. Gene expression and promoter occupancy analyses confirmed that HNF4α is a direct activator of the Pparα gene in vivo and that its expression is subject to feedback regulation by PPARα and Hes6 proteins. These results establish the fundamental role of dynamic regulatory interactions between HNF4α, Hes6, PPARα, and PPARγ in the coordinated expression of genes involved in fatty acid transport and metabolism.

scholarly journals Adiponectin-Mediated Antilipotoxic Effects in Regenerating Pancreatic Islets

Endocrinology ◽  
2015 ◽  
Vol 156 (6) ◽  
pp. 2019-2028 ◽  
Author(s):  
Risheng Ye ◽  
Miao Wang ◽  
Qiong A. Wang ◽  
Philipp E. Scherer
Keyword(s):  
Lipid Metabolism ◽  
Pancreatic Islets ◽  
Cell Mass ◽  
Cell Regeneration ◽  
Peroxisome Proliferator ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Β Cell ◽  
Tissue Mass ◽  
Hepatocyte Nuclear Factor 4Α

Abstract Pathways that stimulate β-cell regeneration remain of great clinical interest, yet effective therapeutic avenues that promote survival or reconstitution of β-cell mass remain elusive. Using a mouse model with inducible β-cell apoptosis followed by adiponectin-mediated regeneration, we aimed to identify key molecules boosting β-cell viability. In the regenerating pancreatic islets, we examined changes within the transcriptome and observed an extensive up-regulation of genes encoding proteins involved in lipid transport and metabolism. The most prominent targets were further confirmed by quantitative PCR and immunofluorescence. Among the upstream regulators predicted by pathway analysis of the transcriptome, we detected enhanced levels of 2 key transcription factors, Hepatocyte Nuclear Factor 4α and Peroxisome Proliferator-Activated Receptorα. Our data suggest that improving pancreatic islet lipid metabolism as an important antilipotoxic phenomenon to boost β-cell regeneration. This is primarily mediated by the adipokine adiponectin that exerts its action on both the beta-cell directly as well as on the adipocyte. Adiponectin induces lipid metabolism gene expression in regenerating islets through Hepatocyte Nuclear Factor 4α and Peroxisome Proliferator-Activated Receptorα. Adiponectin also modulates leptin levels via preserving adipose tissue mass in the insulinopenic state.

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