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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Autor*in:	Rodrigo M. Florentino [verfasserIn] Nicolas A. Fraunhoffer [verfasserIn] Kazutoyo Morita [verfasserIn] Kazuki Takeishi [verfasserIn] Alina Ostrowska [verfasserIn] Abhinav Achreja [verfasserIn] Olamide Animasahun [verfasserIn] Nils Haep [verfasserIn] Shohrat Arazov [verfasserIn] Nandini Agarwal [verfasserIn] Alexandra Collin de l'Hortet [verfasserIn] Jorge Guzman‐Lepe [verfasserIn] Edgar N. Tafaleng [verfasserIn] Amitava Mukherjee [verfasserIn] Kris Troy [verfasserIn] Swati Banerjee [verfasserIn] Shirish Paranjpe [verfasserIn] George K. Michalopoulos [verfasserIn] Aaron Bell [verfasserIn] Deepak Nagrath [verfasserIn] Sarah J. Hainer [verfasserIn] Ira J. Fox [verfasserIn] Alejandro Soto‐Gutierrez [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2020

Übergeordnetes Werk:	In: Hepatology Communications - Wolters Kluwer Health/LWW, 2017, 4(2020), 6, Seite 859-875
Übergeordnetes Werk:	volume:4 ; year:2020 ; number:6 ; pages:859-875

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1002/hep4.1505

Katalog-ID:	DOAJ018088198

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520			\|a 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.
653		0	\|a Diseases of the digestive system. Gastroenterology
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700	0		\|a Kazuki Takeishi \|e verfasserin \|4 aut
700	0		\|a Alina Ostrowska \|e verfasserin \|4 aut
700	0		\|a Abhinav Achreja \|e verfasserin \|4 aut
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700	0		\|a Shirish Paranjpe \|e verfasserin \|4 aut
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700	0		\|a Ira J. Fox \|e verfasserin \|4 aut
700	0		\|a Alejandro Soto‐Gutierrez \|e verfasserin \|4 aut
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allfields	10.1002/hep4.1505 doi (DE-627)DOAJ018088198 (DE-599)DOAJa366b3ff63454cfe85adee4824c052ae DE-627 ger DE-627 rakwb eng RC799-869 Rodrigo M. Florentino verfasserin aut Cellular Location of HNF4α is Linked With Terminal Liver Failure in Humans 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Diseases of the digestive system. Gastroenterology Nicolas A. Fraunhoffer verfasserin aut Kazutoyo Morita verfasserin aut Kazuki Takeishi verfasserin aut Alina Ostrowska verfasserin aut Abhinav Achreja verfasserin aut Olamide Animasahun verfasserin aut Nils Haep verfasserin aut Shohrat Arazov verfasserin aut Nandini Agarwal verfasserin aut Alexandra Collin de l'Hortet verfasserin aut Jorge Guzman‐Lepe verfasserin aut Edgar N. Tafaleng verfasserin aut Amitava Mukherjee verfasserin aut Kris Troy verfasserin aut Swati Banerjee verfasserin aut Shirish Paranjpe verfasserin aut George K. Michalopoulos verfasserin aut Aaron Bell verfasserin aut Deepak Nagrath verfasserin aut Sarah J. Hainer verfasserin aut Ira J. Fox verfasserin aut Alejandro Soto‐Gutierrez verfasserin aut In Hepatology Communications Wolters Kluwer Health/LWW, 2017 4(2020), 6, Seite 859-875 (DE-627)877444587 (DE-600)2881134-3 2471254X nnns volume:4 year:2020 number:6 pages:859-875 https://doi.org/10.1002/hep4.1505 kostenfrei https://doaj.org/article/a366b3ff63454cfe85adee4824c052ae kostenfrei https://doi.org/10.1002/hep4.1505 kostenfrei https://doaj.org/toc/2471-254X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2021 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2088 GBV_ILN_2118 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 4 2020 6 859-875
spelling	10.1002/hep4.1505 doi (DE-627)DOAJ018088198 (DE-599)DOAJa366b3ff63454cfe85adee4824c052ae DE-627 ger DE-627 rakwb eng RC799-869 Rodrigo M. Florentino verfasserin aut Cellular Location of HNF4α is Linked With Terminal Liver Failure in Humans 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Diseases of the digestive system. Gastroenterology Nicolas A. Fraunhoffer verfasserin aut Kazutoyo Morita verfasserin aut Kazuki Takeishi verfasserin aut Alina Ostrowska verfasserin aut Abhinav Achreja verfasserin aut Olamide Animasahun verfasserin aut Nils Haep verfasserin aut Shohrat Arazov verfasserin aut Nandini Agarwal verfasserin aut Alexandra Collin de l'Hortet verfasserin aut Jorge Guzman‐Lepe verfasserin aut Edgar N. Tafaleng verfasserin aut Amitava Mukherjee verfasserin aut Kris Troy verfasserin aut Swati Banerjee verfasserin aut Shirish Paranjpe verfasserin aut George K. Michalopoulos verfasserin aut Aaron Bell verfasserin aut Deepak Nagrath verfasserin aut Sarah J. Hainer verfasserin aut Ira J. Fox verfasserin aut Alejandro Soto‐Gutierrez verfasserin aut In Hepatology Communications Wolters Kluwer Health/LWW, 2017 4(2020), 6, Seite 859-875 (DE-627)877444587 (DE-600)2881134-3 2471254X nnns volume:4 year:2020 number:6 pages:859-875 https://doi.org/10.1002/hep4.1505 kostenfrei https://doaj.org/article/a366b3ff63454cfe85adee4824c052ae kostenfrei https://doi.org/10.1002/hep4.1505 kostenfrei https://doaj.org/toc/2471-254X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2021 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2088 GBV_ILN_2118 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 4 2020 6 859-875
allfields_unstemmed	10.1002/hep4.1505 doi (DE-627)DOAJ018088198 (DE-599)DOAJa366b3ff63454cfe85adee4824c052ae DE-627 ger DE-627 rakwb eng RC799-869 Rodrigo M. Florentino verfasserin aut Cellular Location of HNF4α is Linked With Terminal Liver Failure in Humans 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Diseases of the digestive system. Gastroenterology Nicolas A. Fraunhoffer verfasserin aut Kazutoyo Morita verfasserin aut Kazuki Takeishi verfasserin aut Alina Ostrowska verfasserin aut Abhinav Achreja verfasserin aut Olamide Animasahun verfasserin aut Nils Haep verfasserin aut Shohrat Arazov verfasserin aut Nandini Agarwal verfasserin aut Alexandra Collin de l'Hortet verfasserin aut Jorge Guzman‐Lepe verfasserin aut Edgar N. Tafaleng verfasserin aut Amitava Mukherjee verfasserin aut Kris Troy verfasserin aut Swati Banerjee verfasserin aut Shirish Paranjpe verfasserin aut George K. Michalopoulos verfasserin aut Aaron Bell verfasserin aut Deepak Nagrath verfasserin aut Sarah J. Hainer verfasserin aut Ira J. Fox verfasserin aut Alejandro Soto‐Gutierrez verfasserin aut In Hepatology Communications Wolters Kluwer Health/LWW, 2017 4(2020), 6, Seite 859-875 (DE-627)877444587 (DE-600)2881134-3 2471254X nnns volume:4 year:2020 number:6 pages:859-875 https://doi.org/10.1002/hep4.1505 kostenfrei https://doaj.org/article/a366b3ff63454cfe85adee4824c052ae kostenfrei https://doi.org/10.1002/hep4.1505 kostenfrei https://doaj.org/toc/2471-254X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2021 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2088 GBV_ILN_2118 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 4 2020 6 859-875
allfieldsGer	10.1002/hep4.1505 doi (DE-627)DOAJ018088198 (DE-599)DOAJa366b3ff63454cfe85adee4824c052ae DE-627 ger DE-627 rakwb eng RC799-869 Rodrigo M. Florentino verfasserin aut Cellular Location of HNF4α is Linked With Terminal Liver Failure in Humans 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Diseases of the digestive system. Gastroenterology Nicolas A. Fraunhoffer verfasserin aut Kazutoyo Morita verfasserin aut Kazuki Takeishi verfasserin aut Alina Ostrowska verfasserin aut Abhinav Achreja verfasserin aut Olamide Animasahun verfasserin aut Nils Haep verfasserin aut Shohrat Arazov verfasserin aut Nandini Agarwal verfasserin aut Alexandra Collin de l'Hortet verfasserin aut Jorge Guzman‐Lepe verfasserin aut Edgar N. Tafaleng verfasserin aut Amitava Mukherjee verfasserin aut Kris Troy verfasserin aut Swati Banerjee verfasserin aut Shirish Paranjpe verfasserin aut George K. Michalopoulos verfasserin aut Aaron Bell verfasserin aut Deepak Nagrath verfasserin aut Sarah J. Hainer verfasserin aut Ira J. Fox verfasserin aut Alejandro Soto‐Gutierrez verfasserin aut In Hepatology Communications Wolters Kluwer Health/LWW, 2017 4(2020), 6, Seite 859-875 (DE-627)877444587 (DE-600)2881134-3 2471254X nnns volume:4 year:2020 number:6 pages:859-875 https://doi.org/10.1002/hep4.1505 kostenfrei https://doaj.org/article/a366b3ff63454cfe85adee4824c052ae kostenfrei https://doi.org/10.1002/hep4.1505 kostenfrei https://doaj.org/toc/2471-254X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2021 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2088 GBV_ILN_2118 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 4 2020 6 859-875
allfieldsSound	10.1002/hep4.1505 doi (DE-627)DOAJ018088198 (DE-599)DOAJa366b3ff63454cfe85adee4824c052ae DE-627 ger DE-627 rakwb eng RC799-869 Rodrigo M. Florentino verfasserin aut Cellular Location of HNF4α is Linked With Terminal Liver Failure in Humans 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Diseases of the digestive system. Gastroenterology Nicolas A. Fraunhoffer verfasserin aut Kazutoyo Morita verfasserin aut Kazuki Takeishi verfasserin aut Alina Ostrowska verfasserin aut Abhinav Achreja verfasserin aut Olamide Animasahun verfasserin aut Nils Haep verfasserin aut Shohrat Arazov verfasserin aut Nandini Agarwal verfasserin aut Alexandra Collin de l'Hortet verfasserin aut Jorge Guzman‐Lepe verfasserin aut Edgar N. Tafaleng verfasserin aut Amitava Mukherjee verfasserin aut Kris Troy verfasserin aut Swati Banerjee verfasserin aut Shirish Paranjpe verfasserin aut George K. Michalopoulos verfasserin aut Aaron Bell verfasserin aut Deepak Nagrath verfasserin aut Sarah J. Hainer verfasserin aut Ira J. Fox verfasserin aut Alejandro Soto‐Gutierrez verfasserin aut In Hepatology Communications Wolters Kluwer Health/LWW, 2017 4(2020), 6, Seite 859-875 (DE-627)877444587 (DE-600)2881134-3 2471254X nnns volume:4 year:2020 number:6 pages:859-875 https://doi.org/10.1002/hep4.1505 kostenfrei https://doaj.org/article/a366b3ff63454cfe85adee4824c052ae kostenfrei https://doi.org/10.1002/hep4.1505 kostenfrei https://doaj.org/toc/2471-254X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2021 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2088 GBV_ILN_2118 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 4 2020 6 859-875
language	English
source	In Hepatology Communications 4(2020), 6, Seite 859-875 volume:4 year:2020 number:6 pages:859-875
sourceStr	In Hepatology Communications 4(2020), 6, Seite 859-875 volume:4 year:2020 number:6 pages:859-875
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Diseases of the digestive system. Gastroenterology
isfreeaccess_bool	true
container_title	Hepatology Communications
authorswithroles_txt_mv	Rodrigo M. Florentino @@aut@@ Nicolas A. Fraunhoffer @@aut@@ Kazutoyo Morita @@aut@@ Kazuki Takeishi @@aut@@ Alina Ostrowska @@aut@@ Abhinav Achreja @@aut@@ Olamide Animasahun @@aut@@ Nils Haep @@aut@@ Shohrat Arazov @@aut@@ Nandini Agarwal @@aut@@ Alexandra Collin de l'Hortet @@aut@@ Jorge Guzman‐Lepe @@aut@@ Edgar N. Tafaleng @@aut@@ Amitava Mukherjee @@aut@@ Kris Troy @@aut@@ Swati Banerjee @@aut@@ Shirish Paranjpe @@aut@@ George K. Michalopoulos @@aut@@ Aaron Bell @@aut@@ Deepak Nagrath @@aut@@ Sarah J. Hainer @@aut@@ Ira J. Fox @@aut@@ Alejandro Soto‐Gutierrez @@aut@@
publishDateDaySort_date	2020-01-01T00:00:00Z
hierarchy_top_id	877444587
id	DOAJ018088198
language_de	englisch
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Florentino</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Cellular Location of HNF4α is Linked With Terminal Liver Failure in Humans</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2020</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">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. 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callnumber-first	R - Medicine
author	Rodrigo M. Florentino
spellingShingle	Rodrigo M. Florentino misc RC799-869 misc Diseases of the digestive system. Gastroenterology Cellular Location of HNF4α is Linked With Terminal Liver Failure in Humans
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topic_title	RC799-869 Cellular Location of HNF4α is Linked With Terminal Liver Failure in Humans
topic	misc RC799-869 misc Diseases of the digestive system. Gastroenterology
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title	Cellular Location of HNF4α is Linked With Terminal Liver Failure in Humans
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title_full	Cellular Location of HNF4α is Linked With Terminal Liver Failure in Humans
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author_browse	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
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title_sort	cellular location of hnf4α is linked with terminal liver failure in humans
callnumber	RC799-869
title_auth	Cellular Location of HNF4α is Linked With Terminal Liver Failure in Humans
abstract	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.
abstractGer	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.
abstract_unstemmed	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.
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title_short	Cellular Location of HNF4α is Linked With Terminal Liver Failure in Humans
url	https://doi.org/10.1002/hep4.1505 https://doaj.org/article/a366b3ff63454cfe85adee4824c052ae https://doaj.org/toc/2471-254X
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author2	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
author2Str	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
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doi_str	10.1002/hep4.1505
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up_date	2024-07-03T15:52:46.893Z
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Cellular Location of HNF4α is Linked With Terminal Liver Failure in Humans

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