scholarly journals Integrated approach for the identification of human hepatocyte nuclear factor 4α target genes using protein binding microarrays

Hepatology ◽  
2009 ◽  
Vol 51 (2) ◽  
pp. 642-653 ◽  
Author(s):  
Eugene Bolotin ◽  
Hailing Liao ◽  
Tuong Chi Ta ◽  
Chuhu Yang ◽  
Wendy Hwang-Verslues ◽  
...  
Keyword(s):  
Protein Binding ◽  
Target Genes ◽  
Integrated Approach ◽  
Human Hepatocyte ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Hepatocyte Nuclear Factor 4Α ◽  
Protein Binding Microarrays

scholarly journals MicroRNAs Regulate Human Hepatocyte Nuclear Factor 4α, Modulating the Expression of Metabolic Enzymes and Cell Cycle

2009 ◽  
Vol 285 (7) ◽  
pp. 4415-4422 ◽  
Author(s):  
Shingo Takagi ◽  
Miki Nakajima ◽  
Katsuhiko Kida ◽  
Yu Yamaura ◽  
Tatsuki Fukami ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Metabolic Enzymes ◽  
Human Hepatocyte ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Hepatocyte Nuclear Factor 4Α

scholarly journals Hepatocyte-specific deletion of hepatocyte nuclear factor-4α in adult mice results in increased hepatocyte proliferation

2013 ◽  
Vol 304 (1) ◽  
pp. G26-G37 ◽  
Author(s):  
Chad Walesky ◽  
Sumedha Gunewardena ◽  
Ernest F. Terwilliger ◽  
Genea Edwards ◽  
Prachi Borude ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Viral Vector ◽  
Hepatocyte Proliferation ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Hepatocyte Differentiation ◽  
Hepatic Differentiation ◽  
Hepatocyte Nuclear Factor 4Α ◽  
Specific Deletion

Hepatocyte nuclear factor-4α (HNF4α) is known as the master regulator of hepatocyte differentiation. Recent studies indicate that HNF4α may inhibit hepatocyte proliferation via mechanisms that have yet to be identified. Using a HNF4α knockdown mouse model based on delivery of inducible Cre recombinase via an adeno-associated virus 8 viral vector, we investigated the role of HNF4α in the regulation of hepatocyte proliferation. Hepatocyte-specific deletion of HNF4α resulted in increased hepatocyte proliferation. Global gene expression analysis showed that a majority of the downregulated genes were previously known HNF4α target genes involved in hepatic differentiation. Interestingly, ≥500 upregulated genes were associated with cell proliferation and cancer. Furthermore, we identified potential negative target genes of HNF4α, many of which are involved in the stimulation of proliferation. Using chromatin immunoprecipitation analysis, we confirmed binding of HNF4α at three of these genes. Furthermore, overexpression of HNF4α in mouse hepatocellular carcinoma cells resulted in a decrease in promitogenic gene expression and cell cycle arrest. Taken together, these data indicate that, apart from its role in hepatocyte differentiation, HNF4α actively inhibits hepatocyte proliferation by repression of specific promitogenic genes.

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 Induction of Hepatic Metabolic Functions by a Novel Variant of Hepatocyte Nuclear Factor 4γ

2018 ◽  
Vol 38 (24) ◽  
Author(s):  
Shota Sasaki ◽  
Mizuho Urabe ◽  
Tsukasa Maeda ◽  
Junko Suzuki ◽  
Ryota Irie ◽  
...  
Keyword(s):  
Target Genes ◽  
Critical Factor ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Hepatic Expression ◽  
Metabolic Functions ◽  
Transactivation Potential ◽  
Urea Production ◽  
Novel Variant ◽  
Hepatocyte Nuclear Factor 4Α

ABSTRACT Hepatocyte nuclear factor 4α (HNF4α) is a critical factor for hepatocyte differentiation. HNF4α expression is decreased in hepatocellular carcinoma (HCC), which suggests a role in repression of hepatocyte dedifferentiation. In the present study, hepatic expression of HNF4γ was increased in liver-specific Hnf4a-null mice. The HNF4γ whose expression was increased contained two variants, a known short variant, designated HNF4γ1, and a novel long variant, designated HNF4γ2. HNF4G2 mRNA was highly expressed in small intestine, and the transactivation potential of HNF4γ2 was the strongest among these variants, but the potential of HNF4γ1 was the lowest. Cotransfection experiments revealed that HNF4γ1 repressed HNF4α- and HNF4γ2-dependent transactivation, while HNF4γ2 promoted HNF4α-dependent transactivation. HNF4γ1 and HNF4γ2 were able to bind to the HNF4α binding sites with an affinity similar to that of HNF4α. Furthermore, HNF4γ2, but not HNF4γ1, robustly induced the expression of typical HNF4α target genes to a greater degree than HNF4α. Additionally, HNF4γ2 suppressed proliferation of hepatoma cells as well as HNF4α and HNF4γ1 did, and HNF4γ2 induced critical hepatic functions, such as glucose and urea production, and cytochrome P450 1A2 activity more strongly than HNF4α and HNF4γ1 did. These results indicate that HNF4γ2 has potential for redifferentiation of HCC and thus may be explored as a target for HCC therapy.

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