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HGFAC is a ChREBP-regulated hepatokine that enhances glucose and lipid homeostasis

Carbohydrate response element–binding protein (ChREBP) is a carbohydrate-sensing transcription factor that regulates both adaptive and maladaptive genomic responses in coordination of systemic fuel homeostasis. Genetic variants in the ChREBP locus associate with diverse metabolic traits in humans, i...

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Autores principales: Sargsyan, Ashot, Doridot, Ludivine, Hannou, Sarah A., Tong, Wenxin, Srinivasan, Harini, Ivison, Rachael, Monn, Ruby, Kou, Henry H., Haldeman, Jonathan M., Arlotto, Michelle, White, Phillip J., Grimsrud, Paul A., Astapova, Inna, Tsai, Linus T., Herman, Mark A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9870088/
https://www.ncbi.nlm.nih.gov/pubmed/36413406
http://dx.doi.org/10.1172/jci.insight.153740
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author Sargsyan, Ashot
Doridot, Ludivine
Hannou, Sarah A.
Tong, Wenxin
Srinivasan, Harini
Ivison, Rachael
Monn, Ruby
Kou, Henry H.
Haldeman, Jonathan M.
Arlotto, Michelle
White, Phillip J.
Grimsrud, Paul A.
Astapova, Inna
Tsai, Linus T.
Herman, Mark A.
author_facet Sargsyan, Ashot
Doridot, Ludivine
Hannou, Sarah A.
Tong, Wenxin
Srinivasan, Harini
Ivison, Rachael
Monn, Ruby
Kou, Henry H.
Haldeman, Jonathan M.
Arlotto, Michelle
White, Phillip J.
Grimsrud, Paul A.
Astapova, Inna
Tsai, Linus T.
Herman, Mark A.
author_sort Sargsyan, Ashot
collection PubMed
description Carbohydrate response element–binding protein (ChREBP) is a carbohydrate-sensing transcription factor that regulates both adaptive and maladaptive genomic responses in coordination of systemic fuel homeostasis. Genetic variants in the ChREBP locus associate with diverse metabolic traits in humans, including circulating lipids. To identify novel ChREBP-regulated hepatokines that contribute to its systemic metabolic effects, we integrated ChREBP ChIP-Seq analysis in mouse liver with human genetic and genomic data for lipid traits and identified hepatocyte growth factor activator (HGFAC) as a promising ChREBP-regulated candidate in mice and humans. HGFAC is a protease that activates the pleiotropic hormone hepatocyte growth factor. We demonstrate that HGFAC-KO mice had phenotypes concordant with putative loss-of-function variants in human HGFAC. Moreover, in gain- and loss-of-function genetic mouse models, we demonstrate that HGFAC enhanced lipid and glucose homeostasis, which may be mediated in part through actions to activate hepatic PPARγ activity. Together, our studies show that ChREBP mediated an adaptive response to overnutrition via activation of HGFAC in the liver to preserve glucose and lipid homeostasis.
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spelling pubmed-98700882023-02-06 HGFAC is a ChREBP-regulated hepatokine that enhances glucose and lipid homeostasis Sargsyan, Ashot Doridot, Ludivine Hannou, Sarah A. Tong, Wenxin Srinivasan, Harini Ivison, Rachael Monn, Ruby Kou, Henry H. Haldeman, Jonathan M. Arlotto, Michelle White, Phillip J. Grimsrud, Paul A. Astapova, Inna Tsai, Linus T. Herman, Mark A. JCI Insight Research Article Carbohydrate response element–binding protein (ChREBP) is a carbohydrate-sensing transcription factor that regulates both adaptive and maladaptive genomic responses in coordination of systemic fuel homeostasis. Genetic variants in the ChREBP locus associate with diverse metabolic traits in humans, including circulating lipids. To identify novel ChREBP-regulated hepatokines that contribute to its systemic metabolic effects, we integrated ChREBP ChIP-Seq analysis in mouse liver with human genetic and genomic data for lipid traits and identified hepatocyte growth factor activator (HGFAC) as a promising ChREBP-regulated candidate in mice and humans. HGFAC is a protease that activates the pleiotropic hormone hepatocyte growth factor. We demonstrate that HGFAC-KO mice had phenotypes concordant with putative loss-of-function variants in human HGFAC. Moreover, in gain- and loss-of-function genetic mouse models, we demonstrate that HGFAC enhanced lipid and glucose homeostasis, which may be mediated in part through actions to activate hepatic PPARγ activity. Together, our studies show that ChREBP mediated an adaptive response to overnutrition via activation of HGFAC in the liver to preserve glucose and lipid homeostasis. American Society for Clinical Investigation 2023-01-10 /pmc/articles/PMC9870088/ /pubmed/36413406 http://dx.doi.org/10.1172/jci.insight.153740 Text en © 2023 Sargsyan et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Sargsyan, Ashot
Doridot, Ludivine
Hannou, Sarah A.
Tong, Wenxin
Srinivasan, Harini
Ivison, Rachael
Monn, Ruby
Kou, Henry H.
Haldeman, Jonathan M.
Arlotto, Michelle
White, Phillip J.
Grimsrud, Paul A.
Astapova, Inna
Tsai, Linus T.
Herman, Mark A.
HGFAC is a ChREBP-regulated hepatokine that enhances glucose and lipid homeostasis
title HGFAC is a ChREBP-regulated hepatokine that enhances glucose and lipid homeostasis
title_full HGFAC is a ChREBP-regulated hepatokine that enhances glucose and lipid homeostasis
title_fullStr HGFAC is a ChREBP-regulated hepatokine that enhances glucose and lipid homeostasis
title_full_unstemmed HGFAC is a ChREBP-regulated hepatokine that enhances glucose and lipid homeostasis
title_short HGFAC is a ChREBP-regulated hepatokine that enhances glucose and lipid homeostasis
title_sort hgfac is a chrebp-regulated hepatokine that enhances glucose and lipid homeostasis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9870088/
https://www.ncbi.nlm.nih.gov/pubmed/36413406
http://dx.doi.org/10.1172/jci.insight.153740
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