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ResearchIn-Press PreviewMetabolism Open Access | 10.1172/jci.insight.153740

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

Ashot Sargsyan,1 Ludivine Doridot,2 Sarah Anissa Hannou,1 Wenxin Tong,1 Harini Srinivasan,3 Rachael Ivison,4 Ruby Monn,1 Henry H. Kou,1 Jonathan M. Haldeman,1 Michelle Arlotto,1 Phillip J. White,5 Paul A. Grimsrud,5 Inna Astapova,6 Linus T.-Y. Tsai,3 and Mark A. Herman6

1Duke Molecular Physiology Institute, Duke University Medical Center, Durham, United States of America

2Institut Cochin, INSERM, Paris, France

3Medicine, Beth Israel Deaconess Medical Center, Boston, United States of America

4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, United States of America

5Duke University Medical Center, Durham, United States of America

6Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, United States of America

Find articles by Sargsyan, A. in: PubMed | Google Scholar

1Duke Molecular Physiology Institute, Duke University Medical Center, Durham, United States of America

2Institut Cochin, INSERM, Paris, France

3Medicine, Beth Israel Deaconess Medical Center, Boston, United States of America

4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, United States of America

5Duke University Medical Center, Durham, United States of America

6Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, United States of America

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1Duke Molecular Physiology Institute, Duke University Medical Center, Durham, United States of America

2Institut Cochin, INSERM, Paris, France

3Medicine, Beth Israel Deaconess Medical Center, Boston, United States of America

4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, United States of America

5Duke University Medical Center, Durham, United States of America

6Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, United States of America

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1Duke Molecular Physiology Institute, Duke University Medical Center, Durham, United States of America

2Institut Cochin, INSERM, Paris, France

3Medicine, Beth Israel Deaconess Medical Center, Boston, United States of America

4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, United States of America

5Duke University Medical Center, Durham, United States of America

6Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, United States of America

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1Duke Molecular Physiology Institute, Duke University Medical Center, Durham, United States of America

2Institut Cochin, INSERM, Paris, France

3Medicine, Beth Israel Deaconess Medical Center, Boston, United States of America

4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, United States of America

5Duke University Medical Center, Durham, United States of America

6Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, United States of America

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1Duke Molecular Physiology Institute, Duke University Medical Center, Durham, United States of America

2Institut Cochin, INSERM, Paris, France

3Medicine, Beth Israel Deaconess Medical Center, Boston, United States of America

4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, United States of America

5Duke University Medical Center, Durham, United States of America

6Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, United States of America

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1Duke Molecular Physiology Institute, Duke University Medical Center, Durham, United States of America

2Institut Cochin, INSERM, Paris, France

3Medicine, Beth Israel Deaconess Medical Center, Boston, United States of America

4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, United States of America

5Duke University Medical Center, Durham, United States of America

6Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, United States of America

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1Duke Molecular Physiology Institute, Duke University Medical Center, Durham, United States of America

2Institut Cochin, INSERM, Paris, France

3Medicine, Beth Israel Deaconess Medical Center, Boston, United States of America

4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, United States of America

5Duke University Medical Center, Durham, United States of America

6Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, United States of America

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1Duke Molecular Physiology Institute, Duke University Medical Center, Durham, United States of America

2Institut Cochin, INSERM, Paris, France

3Medicine, Beth Israel Deaconess Medical Center, Boston, United States of America

4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, United States of America

5Duke University Medical Center, Durham, United States of America

6Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, United States of America

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1Duke Molecular Physiology Institute, Duke University Medical Center, Durham, United States of America

2Institut Cochin, INSERM, Paris, France

3Medicine, Beth Israel Deaconess Medical Center, Boston, United States of America

4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, United States of America

5Duke University Medical Center, Durham, United States of America

6Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, United States of America

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1Duke Molecular Physiology Institute, Duke University Medical Center, Durham, United States of America

2Institut Cochin, INSERM, Paris, France

3Medicine, Beth Israel Deaconess Medical Center, Boston, United States of America

4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, United States of America

5Duke University Medical Center, Durham, United States of America

6Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, United States of America

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1Duke Molecular Physiology Institute, Duke University Medical Center, Durham, United States of America

2Institut Cochin, INSERM, Paris, France

3Medicine, Beth Israel Deaconess Medical Center, Boston, United States of America

4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, United States of America

5Duke University Medical Center, Durham, United States of America

6Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, United States of America

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1Duke Molecular Physiology Institute, Duke University Medical Center, Durham, United States of America

2Institut Cochin, INSERM, Paris, France

3Medicine, Beth Israel Deaconess Medical Center, Boston, United States of America

4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, United States of America

5Duke University Medical Center, Durham, United States of America

6Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, United States of America

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1Duke Molecular Physiology Institute, Duke University Medical Center, Durham, United States of America

2Institut Cochin, INSERM, Paris, France

3Medicine, Beth Israel Deaconess Medical Center, Boston, United States of America

4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, United States of America

5Duke University Medical Center, Durham, United States of America

6Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, United States of America

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1Duke Molecular Physiology Institute, Duke University Medical Center, Durham, United States of America

2Institut Cochin, INSERM, Paris, France

3Medicine, Beth Israel Deaconess Medical Center, Boston, United States of America

4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, United States of America

5Duke University Medical Center, Durham, United States of America

6Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, United States of America

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Published November 22, 2022 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.153740.
Copyright © 2022, Sargsyan et al. 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/.
Published November 22, 2022 - Version history
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Abstract

Carbohydrate Responsive 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 (HGF). We demonstrate that HGFAC KO mice have 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 enhances lipid and glucose homeostasis, which may be mediated in part through actions to activate hepatic PPARγ activity. Together, our studies show that ChREBP mediates an adaptive response to overnutrition via activation of HGFAC in the liver to preserve glucose and lipid homeostasis.

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graphical abstract
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Version history
  • Version 1 (November 22, 2022): In-Press Preview
  • Version 2 (January 10, 2023): Electronic publication
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