HGFAC is a ChREBP Regulated Hepatokine that Enhances Glucose and Lipid Homeostasis [RNA-Seq]

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.碳水化合物反应元件结合蛋白（Carbohydrate Responsive Element-Binding Protein, ChREBP）是一类碳水化合物感知转录因子，可协同调控全身能量稳态，介导适应性与不良适应性基因组应答反应。ChREBP基因座的遗传变异与人类多种代谢性状相关，包括循环脂质水平异常。为鉴定介导其全身代谢效应的新型ChREBP调控肝因子，本研究将小鼠肝脏中的ChREBP染色质免疫共沉淀测序（ChIP-seq）分析结果，与人类针对脂质性状的遗传及基因组数据进行整合分析，最终鉴定出肝细胞生长因子激活因子（Hepatocyte Growth Factor Activator, HGFAC）作为小鼠与人类中潜在的ChREBP调控候选靶标。HGFAC是一种可激活多效激素肝细胞生长因子（Hepatocyte Growth Factor, HGF）的蛋白酶。本研究证实，HGFAC敲除（KO）小鼠的表型与人类HGFAC基因推定的功能丧失性变异所对应的表型相一致。此外，通过功能获得与功能丧失型基因工程小鼠模型，本研究证明HGFAC可改善脂质与葡萄糖稳态，该效应可能部分通过激活肝脏PPARgamma活性实现。综上，本研究表明ChREBP可通过激活肝脏内的HGFAC，介导机体对营养过剩的适应性应答，从而维持葡萄糖与脂质稳态。8周龄雄性HGFAC敲除小鼠及其同窝对照小鼠分别被喂食高脂高糖（HF/HS）饲料或普通对照饲料。