TRIB1 is a positive regulator of hepatocyte nuclear factor 4-alpha

Abstract The TRIB1 locus has been linked to both cardiovascular disease and hepatic steatosis. Recent efforts have revealed TRIB1 to be a major regulator of liver function, largely, but not exclusively, via CEBPA degradation. We recently uncovered a functional interaction between TRIB1 and HNF4A, an...

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Autores principales:	Sébastien Soubeyrand, Amy Martinuk, Ruth McPherson
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3ef6b6c9fa4342a49ea9bf015bfea87b
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spelling	oai:doaj.org-article:3ef6b6c9fa4342a49ea9bf015bfea87b2021-12-02T16:07:45ZTRIB1 is a positive regulator of hepatocyte nuclear factor 4-alpha10.1038/s41598-017-05768-12045-2322https://doaj.org/article/3ef6b6c9fa4342a49ea9bf015bfea87b2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05768-1https://doaj.org/toc/2045-2322Abstract The TRIB1 locus has been linked to both cardiovascular disease and hepatic steatosis. Recent efforts have revealed TRIB1 to be a major regulator of liver function, largely, but not exclusively, via CEBPA degradation. We recently uncovered a functional interaction between TRIB1 and HNF4A, another key regulator of hepatic function, whose molecular underpinnings remained to be clarified. Here we have extended these findings. In hepatoma models, HNF4A levels were found to depend on TRIB1, independently of its impact on CEBPA. Using a reporter assay model, MTTP reporter activity, which depends on HNF4A, positively correlated with TRIB1 levels. Confocal microscopy demonstrated partial colocalization of TRIB1 and HNF4A. Using overexpressed proteins we demonstrate that TRIB1 and HNF4A can form complexes in vivo. Mapping of the interaction interfaces identified two distinct regions within TRIB1 which associated with the N-terminal region of HNF4A. Lastly, the TRIB1-HNF4A interaction resisted competition with a CEPBA-derived peptide, suggesting different binding modalities. Together these findings establish that TRIB1 is required for HNF4A function. This regulatory axis represents a novel CEBPA-independent aspect of TRIB1 function predicted to play an important role in liver physiology.Sébastien SoubeyrandAmy MartinukRuth McPhersonNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sébastien Soubeyrand Amy Martinuk Ruth McPherson TRIB1 is a positive regulator of hepatocyte nuclear factor 4-alpha
description	Abstract The TRIB1 locus has been linked to both cardiovascular disease and hepatic steatosis. Recent efforts have revealed TRIB1 to be a major regulator of liver function, largely, but not exclusively, via CEBPA degradation. We recently uncovered a functional interaction between TRIB1 and HNF4A, another key regulator of hepatic function, whose molecular underpinnings remained to be clarified. Here we have extended these findings. In hepatoma models, HNF4A levels were found to depend on TRIB1, independently of its impact on CEBPA. Using a reporter assay model, MTTP reporter activity, which depends on HNF4A, positively correlated with TRIB1 levels. Confocal microscopy demonstrated partial colocalization of TRIB1 and HNF4A. Using overexpressed proteins we demonstrate that TRIB1 and HNF4A can form complexes in vivo. Mapping of the interaction interfaces identified two distinct regions within TRIB1 which associated with the N-terminal region of HNF4A. Lastly, the TRIB1-HNF4A interaction resisted competition with a CEPBA-derived peptide, suggesting different binding modalities. Together these findings establish that TRIB1 is required for HNF4A function. This regulatory axis represents a novel CEBPA-independent aspect of TRIB1 function predicted to play an important role in liver physiology.
format	article
author	Sébastien Soubeyrand Amy Martinuk Ruth McPherson
author_facet	Sébastien Soubeyrand Amy Martinuk Ruth McPherson
author_sort	Sébastien Soubeyrand
title	TRIB1 is a positive regulator of hepatocyte nuclear factor 4-alpha
title_short	TRIB1 is a positive regulator of hepatocyte nuclear factor 4-alpha
title_full	TRIB1 is a positive regulator of hepatocyte nuclear factor 4-alpha
title_fullStr	TRIB1 is a positive regulator of hepatocyte nuclear factor 4-alpha
title_full_unstemmed	TRIB1 is a positive regulator of hepatocyte nuclear factor 4-alpha
title_sort	trib1 is a positive regulator of hepatocyte nuclear factor 4-alpha
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/3ef6b6c9fa4342a49ea9bf015bfea87b
work_keys_str_mv	AT sebastiensoubeyrand trib1isapositiveregulatorofhepatocytenuclearfactor4alpha AT amymartinuk trib1isapositiveregulatorofhepatocytenuclearfactor4alpha AT ruthmcpherson trib1isapositiveregulatorofhepatocytenuclearfactor4alpha
_version_	1718384710788317184

TRIB1 is a positive regulator of hepatocyte nuclear factor 4-alpha

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