GSE196012
Brap regulates liver morphology and hepatocyte turnover via modulation of the Hippo pathway
Regulation of hepatocyte proliferation and liver morphology is of critical importance to tissue and whole-body homeostasis. However, the molecular mechanisms that underlie this complex process are incompletely understood. Here we describe a novel role for the ubiquitin ligase BRAP in regulation of hepatocyte morphology and turnover via regulation of MST2, a protein kinase in the Hippo pathway.  The Hippo pathway has been implicated in control of liver morphology, inflammation and fibrosis. We demonstrate here that liver-specific ablation of Brap in mice results in gross and cellular morphological alterations of the liver. Brap-deficient livers exhibit increased hepatocyte proliferation, cell death, and inflammation. We show that loss of BRAP protein alters Hippo pathway signaling, causing a reduction in phosphorylation of YAP and increased expression of YAP target genes, including those regulating cell growth and interactions with the extracellular environment. Finally, increased Hippo signaling in Brap knockout mice alters the pattern of liver lipid accumulation in dietary models of obesity. These studies identify a role for BRAP as a modulator of the hepatic Hippo pathway with relevance to human liver disease.  tissue and whole-body homeostasis. However, the molecular mechanisms that underlie this  complex process are incompletely understood. Here we describe a novel role for the ubiquitin  ligase BRAP in regulation of hepatocyte morphology and turnover via regulation of MST2, a  protein kinase in the Hippo pathway. The Hippo pathway has been implicated in control of liver  morphology, inflammation and fibrosis. We demonstrate here that liver-specific ablation of Brap  in mice results in gross and cellular morphological alterations of the liver. Brap-deficient livers  exhibit increased hepatocyte proliferation, cell death, and inflammation. We show that loss of  BRAP protein alters Hippo pathway signaling, causing a reduction in phosphorylation of YAP  and increased expression of YAP target genes, including those regulating cell growth and  interactions with the extracellular environment. Finally, increased Hippo signaling in Brap  knockout mice alters the pattern of liver lipid accumulation in dietary models of obesity. These  studies identify a role for BRAP as a modulator of the hepatic Hippo pathway with relevance to  human liver disease. Overall design: RNA-Seq of Liver specific Brap knockout mice liver vs control. (Brap fl/fl; Alb Cre+ vs Brap fl/fl; Alb Cre-) (n=4).