Regulation of Mouse Hepatic α-Amino-β-Carboxymuconate-ϵ-Semialdehyde Decarboxylase, a Key Enzyme in the Tryptophan-Nicotinamide Adenine Dinucleotide Pathway, by Hepatocyte Nuclear Factor 4α and Peroxisome Proliferator-Activated Receptor α

2006 ◽  
Vol 70 (4) ◽  
pp. 1281-1290 ◽  
Author(s):  
Mariko Shin ◽  
Insook Kim ◽  
Yusuke Inoue ◽  
Shioko Kimura ◽  
Frank J. Gonzalez
2003 ◽  
Vol 369 (1) ◽  
pp. 17-22 ◽  
Author(s):  
Jared N. BOUSTEAD ◽  
Beth T. STADELMAIER ◽  
Angela M. EEDS ◽  
Peter O. WIEBE ◽  
Christina A. SVITEK ◽  
...  

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.


2008 ◽  
Vol 415 (2) ◽  
pp. 289-296 ◽  
Author(s):  
Zhongyan Wang ◽  
Peter A. Burke

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.


2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Shinya Okishio ◽  
Kanji Yamaguchi ◽  
Hiroshi Ishiba ◽  
Nozomi Tochiki ◽  
Kota Yano ◽  
...  

Abstract We explored the beneficial effects of GW7647, a peroxisome proliferator activated receptor α (PPARα) agonist, and metformin, an anti-diabetic drug on an advanced nonalcoholic steatohepatitis (NASH) model in rodents and investigated the possible mechanisms involved. Mice were fed control chow or a choline-deficient l-amino acid-defined diet containing 45% fat (HF-CDAA). The mice fed HF-CDAA diets for 16 weeks were divided into four groups: the no treatment (HF-CDAA), HF-CDAA containing 1000 mg/kg metformin, HF-CDAA containing 10 mg/kg GW7647, and HF-CDAA with both metformin and GW7647 groups. Metformin alone slightly deteriorated the aspartate and alanine aminotransferase (AST/ALT) values, whereas co-treatment with GW7647 and metformin greatly suppressed liver injury and fibrosis via activation of the AMP-activated protein kinase (AMPK) pathway. Further study revealed that co-treatment decreased the expression of inflammatory-, fibrogenesis-, and endoplasmic reticulum (ER) stress-related genes and increased the oxidized nicotinamide adenine dinucleotide (NAD)/reduced nicotinamide adenine dinucleotide (NADH) ratio, suggesting the superiority of co-treatment due to restoration of mitochondrial function. The additive benefits of a PPARα agonist and metformin in a HF-CDAA diet-induced advanced NASH model was firstly demonstrated, possibly through restoration of mitochondrial function and AMPK activation, which finally resulted in suppression of hepatic inflammation, ER stress, then, fibrosis.


2009 ◽  
Vol 30 (3) ◽  
pp. 565-577 ◽  
Author(s):  
Celia Pilar Martinez-Jimenez ◽  
Irene Kyrmizi ◽  
Philippe Cardot ◽  
Frank J. Gonzalez ◽  
Iannis Talianidis

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.


Endocrinology ◽  
2015 ◽  
Vol 156 (6) ◽  
pp. 2019-2028 ◽  
Author(s):  
Risheng Ye ◽  
Miao Wang ◽  
Qiong A. Wang ◽  
Philipp E. Scherer

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.


Sign in / Sign up

Export Citation Format

Share Document