Cellular Location of HNF4α is Linked With Terminal Liver Failure in Humans
Hepatocyte nuclear factor 4 alpha (HNF4α) is a transcription factor that plays a critical role in hepatocyte function, and HNF4α‐based reprogramming corrects terminal liver failure in rats with chronic liver disease. In the livers of patients with advanced cirrhosis, HNF4α RNA expression levels decr...
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Format: | Article |
Language: | English |
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Wiley
2020-06-01
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Series: | Hepatology Communications |
Online Access: | https://doi.org/10.1002/hep4.1505 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Rodrigo M. Florentino Nicolas A. Fraunhoffer Kazutoyo Morita Kazuki Takeishi Alina Ostrowska Abhinav Achreja Olamide Animasahun Nils Haep Shohrat Arazov Nandini Agarwal Alexandra Collin de l'Hortet Jorge Guzman‐Lepe Edgar N. Tafaleng Amitava Mukherjee Kris Troy Swati Banerjee Shirish Paranjpe George K. Michalopoulos Aaron Bell Deepak Nagrath Sarah J. Hainer Ira J. Fox Alejandro Soto‐Gutierrez |
spellingShingle |
Rodrigo M. Florentino Nicolas A. Fraunhoffer Kazutoyo Morita Kazuki Takeishi Alina Ostrowska Abhinav Achreja Olamide Animasahun Nils Haep Shohrat Arazov Nandini Agarwal Alexandra Collin de l'Hortet Jorge Guzman‐Lepe Edgar N. Tafaleng Amitava Mukherjee Kris Troy Swati Banerjee Shirish Paranjpe George K. Michalopoulos Aaron Bell Deepak Nagrath Sarah J. Hainer Ira J. Fox Alejandro Soto‐Gutierrez Cellular Location of HNF4α is Linked With Terminal Liver Failure in Humans Hepatology Communications |
author_facet |
Rodrigo M. Florentino Nicolas A. Fraunhoffer Kazutoyo Morita Kazuki Takeishi Alina Ostrowska Abhinav Achreja Olamide Animasahun Nils Haep Shohrat Arazov Nandini Agarwal Alexandra Collin de l'Hortet Jorge Guzman‐Lepe Edgar N. Tafaleng Amitava Mukherjee Kris Troy Swati Banerjee Shirish Paranjpe George K. Michalopoulos Aaron Bell Deepak Nagrath Sarah J. Hainer Ira J. Fox Alejandro Soto‐Gutierrez |
author_sort |
Rodrigo M. Florentino |
title |
Cellular Location of HNF4α is Linked With Terminal Liver Failure in Humans |
title_short |
Cellular Location of HNF4α is Linked With Terminal Liver Failure in Humans |
title_full |
Cellular Location of HNF4α is Linked With Terminal Liver Failure in Humans |
title_fullStr |
Cellular Location of HNF4α is Linked With Terminal Liver Failure in Humans |
title_full_unstemmed |
Cellular Location of HNF4α is Linked With Terminal Liver Failure in Humans |
title_sort |
cellular location of hnf4α is linked with terminal liver failure in humans |
publisher |
Wiley |
series |
Hepatology Communications |
issn |
2471-254X |
publishDate |
2020-06-01 |
description |
Hepatocyte nuclear factor 4 alpha (HNF4α) is a transcription factor that plays a critical role in hepatocyte function, and HNF4α‐based reprogramming corrects terminal liver failure in rats with chronic liver disease. In the livers of patients with advanced cirrhosis, HNF4α RNA expression levels decrease as hepatic function deteriorates, and protein expression is found in the cytoplasm. These findings could explain impaired hepatic function in patients with degenerative liver disease. In this study, we analyzed HNF4α localization and the pathways involved in post‐translational modification of HNF4α in human hepatocytes from patients with decompensated liver function. RNA‐sequencing analysis revealed that AKT‐related pathways, specifically phospho‐AKT, is down‐regulated in cirrhotic hepatocytes from patients with terminal failure, in whom nuclear levels of HNF4α were significantly reduced, and cytoplasmic expression of HNF4α was increased. cMET was also significantly reduced in failing hepatocytes. Moreover, metabolic profiling showed a glycolytic phenotype in failing human hepatocytes. The contribution of cMET and phospho‐AKT to nuclear localization of HNF4α was confirmed using Spearman's rank correlation test and pathway analysis, and further correlated with hepatic dysfunction by principal component analysis. HNF4α acetylation, a posttranslational modification important for nuclear retention, was also significantly reduced in failing human hepatocytes when compared with normal controls. Conclusion: These results suggest that the alterations in the cMET‐AKT pathway directly correlate with HNF4α localization and level of hepatocyte dysfunction. This study suggests that manipulation of HNF4α and pathways involved in HNF4α posttranslational modification may restore hepatocyte function in patients with terminal liver failure. |
url |
https://doi.org/10.1002/hep4.1505 |
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doaj-a366b3ff63454cfe85adee4824c052ae2020-11-25T03:18:26ZengWileyHepatology Communications2471-254X2020-06-014685987510.1002/hep4.1505Cellular Location of HNF4α is Linked With Terminal Liver Failure in HumansRodrigo M. Florentino0Nicolas A. Fraunhoffer1Kazutoyo Morita2Kazuki Takeishi3Alina Ostrowska4Abhinav Achreja5Olamide Animasahun6Nils Haep7Shohrat Arazov8Nandini Agarwal9Alexandra Collin de l'Hortet10Jorge Guzman‐Lepe11Edgar N. Tafaleng12Amitava Mukherjee13Kris Troy14Swati Banerjee15Shirish Paranjpe16George K. Michalopoulos17Aaron Bell18Deepak Nagrath19Sarah J. Hainer20Ira J. Fox21Alejandro Soto‐Gutierrez22Department of Pathology University of Pittsburgh Pittsburgh PADepartment of Pathology University of Pittsburgh Pittsburgh PADepartment of Pathology University of Pittsburgh Pittsburgh PADepartment of Pathology University of Pittsburgh Pittsburgh PADepartment of Surgery Children's Hospital of Pittsburgh of UPMC University of Pittsburgh Pittsburgh PALaboratory for Systems Biology of Human Diseases Department of Biomedical Engineering Biointerfaces Institute University of Michigan Ann Arbor MILaboratory for Systems Biology of Human Diseases Department of Biomedical Engineering Biointerfaces Institute University of Michigan Ann Arbor MIDepartment of Pathology University of Pittsburgh Pittsburgh PADepartment of Pathology University of Pittsburgh Pittsburgh PADepartment of Pathology University of Pittsburgh Pittsburgh PADepartment of Pathology University of Pittsburgh Pittsburgh PADepartment of Pathology University of Pittsburgh Pittsburgh PADepartment of Surgery Children's Hospital of Pittsburgh of UPMC University of Pittsburgh Pittsburgh PADepartment of Surgery Children's Hospital of Pittsburgh of UPMC University of Pittsburgh Pittsburgh PADepartment of Biological Sciences University of Pittsburgh Pittsburgh PADepartment of Pathology University of Pittsburgh Pittsburgh PADepartment of Pathology University of Pittsburgh Pittsburgh PADepartment of Pathology University of Pittsburgh Pittsburgh PADepartment of Pathology University of Pittsburgh Pittsburgh PALaboratory for Systems Biology of Human Diseases Department of Biomedical Engineering Biointerfaces Institute University of Michigan Ann Arbor MIDepartment of Biological Sciences University of Pittsburgh Pittsburgh PADepartment of Surgery Children's Hospital of Pittsburgh of UPMC University of Pittsburgh Pittsburgh PADepartment of Pathology University of Pittsburgh Pittsburgh PAHepatocyte nuclear factor 4 alpha (HNF4α) is a transcription factor that plays a critical role in hepatocyte function, and HNF4α‐based reprogramming corrects terminal liver failure in rats with chronic liver disease. In the livers of patients with advanced cirrhosis, HNF4α RNA expression levels decrease as hepatic function deteriorates, and protein expression is found in the cytoplasm. These findings could explain impaired hepatic function in patients with degenerative liver disease. In this study, we analyzed HNF4α localization and the pathways involved in post‐translational modification of HNF4α in human hepatocytes from patients with decompensated liver function. RNA‐sequencing analysis revealed that AKT‐related pathways, specifically phospho‐AKT, is down‐regulated in cirrhotic hepatocytes from patients with terminal failure, in whom nuclear levels of HNF4α were significantly reduced, and cytoplasmic expression of HNF4α was increased. cMET was also significantly reduced in failing hepatocytes. Moreover, metabolic profiling showed a glycolytic phenotype in failing human hepatocytes. The contribution of cMET and phospho‐AKT to nuclear localization of HNF4α was confirmed using Spearman's rank correlation test and pathway analysis, and further correlated with hepatic dysfunction by principal component analysis. HNF4α acetylation, a posttranslational modification important for nuclear retention, was also significantly reduced in failing human hepatocytes when compared with normal controls. Conclusion: These results suggest that the alterations in the cMET‐AKT pathway directly correlate with HNF4α localization and level of hepatocyte dysfunction. This study suggests that manipulation of HNF4α and pathways involved in HNF4α posttranslational modification may restore hepatocyte function in patients with terminal liver failure.https://doi.org/10.1002/hep4.1505 |