scholarly journals Hepatocyte Nuclear Factor 4 Alpha Attenuated Lipotoxicity, But Increased Bile Acid Toxicity in Non-Alcoholic Fatty Liver Disease Model.

2021 ◽  
Author(s):  
Yun Jin Noh ◽  
Jae Sun Lee ◽  
Dae Won Jun ◽  
Sung Ryol Lee ◽  
Ju Hee Oh ◽  
...  
Keyword(s):  
Bile Acid ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Alcoholic Fatty Liver ◽  
Hepatic Fat ◽  
Hepatocyte Nuclear Factor 4 ◽  
Acid Toxicity ◽  
Nafld Activity Score ◽  
Alcoholic Fatty Liver Disease

Abstract Background: It is known that hepatocyte nuclear factor 4 alpha (HNF4α) is key master nuclear receptor for hepatic fat and bile acid metabolic pathways. But the role of HNF4α in non-alcoholic fatty liver disease (NAFLD) is complex. The current study aimed to investigate role of HNF4α in NAFLD. Methods: Hepatic HNF4α expression evaluated in human NAFLD subjects. Free fatty acid induced lipotoxicity evaluated under HNF4α over- and down regulation. Chenodeoxy cholic acid (CDCA) induced bile acid toxicity evaluated under HNF4α in In Vitro NAFLD model. NAFLD activity score and fibrosis assessed after HNF4α silencing in methionine choline deficiency diet fed mice. Results: Hepatic HNF4α expression was higher in NAFLD than in control group. Overexpression of HNF4α reduced intracellular lipid contents via increasing mitochondria beta-oxidation and hepatic fat excretion. HNF4α overexpression attenuated palmitic acid (PA) induced lipotoxicity. Protective effects of HNF4α on cell death were reversed when CDCA co-treated with PA. CDCA mono-treatment did not affect cell viability, but co-treatment with PA and CDCA decreased cell viability. Bile acid toxicity of HNF4α was exaggerated under PA co-treatment with CDCA. HNF4α knock down using small interfering RNA recovered cell apoptosis and increased cell proliferation from PA and CDCA co-treatment condition. Inhibition of HNF4α using sh-HNF4α adenovirus vector did not reduce hepatic fat accumulation, but decreased intrahepatic inflammation and NAFLD activity score compared to control.Conclusions: HNF4α increased free fatty acid oxidation and attenuated lipotixicity, but increased bile acid toxicity in NAFLD animal model. Inhibition of HNF4α attenuated In vivo NAFLD model.

scholarly journals Hepatocyte Nuclear Factor 4 alpha (HNF4α) Activation is Essential for Termination of Liver Regeneration

2018 ◽  
Author(s):  
Ian Huck ◽  
Sumedha Gunewardena ◽  
Regina Espanol-Suner ◽  
Holger Willenbring ◽  
Udayan Apte
Keyword(s):  
Gene Expression ◽  
Liver Regeneration ◽  
Target Gene ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Hepatic Differentiation ◽  
Target Gene Expression ◽  
Protein Levels ◽  
Hepatocyte Nuclear Factor 4

AbstractHepatocyte Nuclear Factor 4 alpha (HNF4α) is critical for hepatic differentiation. Recent studies have highlighted its role in inhibition of hepatocyte proliferation and tumor suppression. However, the role of HNF4α in liver regeneration is not known. We hypothesized that hepatocytes modulate HNF4α activity when navigating between differentiated and proliferative states during liver regeneration. Western blot analysis revealed a rapid decline in nuclear and cytoplasmic HNF4α protein levels accompanied with decreased target gene expression within 1 hour after 2/3 partial hepatectomy (post-PH) in C57BL/6J mice. HNF4α protein expression did not recover to the pre-PH levels until day 3. Hepatocyte-specific deletion of HNF4α (HNF4α-KO) in mice resulted in 100% mortality post-PH despite increased proliferative marker expression throughout regeneration. Sustained loss of HNF4α target gene expression throughout regeneration indicated HNF4α-KO mice were unable to compensate for loss of HNF4α transcriptional activity. Deletion of HNF4α resulted in sustained proliferation accompanied by c-myc and cyclin D1 over expression and a complete deficiency of hepatocyte function after PH. Interestingly, overexpression of degradation-resistant HNF4α in hepatocytes did not prevent initiation of regeneration after PH. Finally, AAV8-mediated reexpression of HNF4α in hepatocytes of HNF4α-KO mice post-PH restored HNF4α protein levels, induced target gene expression and improved survival of HNF4α-KO mice post-PH. In conclusion, these data indicate that HNF4α reexpression following initial decrease is critical for hepatocytes to exit from cell cycle and resume function during the termination phase of liver regeneration. These results reveal the role of HNF4α in liver regeneration and have implications for therapy of liver failure.

scholarly journals Increased expression of hepatocyte nuclear factor 4 alpha transcribed by promoter 2 indicates a poor prognosis in hepatocellular carcinoma

2017 ◽  
Vol 10 (10) ◽  
pp. 761-771 ◽  
Author(s):  
Shao-hang Cai ◽  
Shi-xun Lu ◽  
Li-li Liu ◽  
Chris Zhiyi Zhang ◽  
Jing-ping Yun
Keyword(s):  
Hepatocellular Carcinoma ◽  
Training Group ◽  
Tissue Microarrays ◽  
Favourable Outcome ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Kaplan Meier ◽  
Hepatocyte Nuclear Factor 4 ◽  
Prognostic Prediction

Background: Hepatocyte nuclear factor 4 alpha (HNF4α) plays an important role in tumourigenesis. There is growing evidence indicating that HNF4α transcribed by promoter 1 (P1-HNF4α) is expressed at relatively low levels in HCC and its presence predicts a favourable outcome for hepatocellular carcinoma (HCC) patients. However, the role of HNF4α transcribed by promoter 2 (P2-HNF4α) in HCC remains unclear. Methods: A total of 615 HCC specimens were obtained to construct tissue microarrays and perform immunohistochemistry. The relationship between P2-HNF4α and clinical features of HCC patients were analysed. Kaplan–Meier analysis was conducted to assess the prognostic value of P2-HNF4α. Results: The results showed that the expression of P2-HNF4α in HCC was noticeably increased in HCC tissues compared with the nontumourous tissues. In addition, P1-HNF4α expression was negatively correlated with P2-HNF4α expression ( p = 0.023). High P2-HNF4α expression was significantly associated with poor differentiation of HCC ( p = 0.002) and vascular invasion ( p = 0.017). Kaplan–Meier analysis showed that P2-HNF4α expression was closely correlated with overall survival in the training group ( p = 0.01), validation group ( p = 0.034), and overall group of patients with HCC ( p < 0.001). Conclusions: Our data show that the role of HNF4α in cancer development needs to be further refined. P2-HNF4α, different from P1-HNF4α, is markedly upregulated and serves as an oncogene-associated protein in HCC. Our study therefore provides a promising biomarker for prognostic prediction and a potential therapeutic target for HCC.

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