| Experiment Id | GSE217982 | Name | HGFAC is a ChREBP Regulated Hepatokine that Enhances Glucose and Lipid Homeostasis [RNA-Seq] |
| Experiment Type | RNA-Seq | Study Type | WT vs. Mutant |
| Source | GEO | Curation Date | 2024-08-22 |
| description | 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 PPARgamma 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. 8-week old HGFAC KO male mice and their littermate controls were fed HF/HS diet or control chow diet. |
