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 role for the ubiquitin ligase BRCA1-associated protein (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 the 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.

Automated summary

The study illustrates the role of BRAP in modulating the hepatic Hippo pathway by regulating MST2, impacting liver cell morphology and turnover. Loss of BRAP leads to significant morphological changes in the liver, increased hepatocyte proliferation, cell death, and inflammation. The altered Hippo pathway signaling in Brap knockout mice affects liver lipid accumulation in dietary models of obesity, highlighting its relevance to human liver disease.