Role of Matrix Gla Protein in Transforming Growth Factor-β Signaling and Nonalcoholic Steatohepatitis in Mice

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is a complex disease involving both genetic and environmental factors in its onset and progression. We analyzed NASH phenotypes in a genetically diverse cohort ofmice, the HybridMouse Diversity Panel, to identify genes contributing to disease susceptibility. METHODS: A systems genetics approach, involving integration of genetic, transcriptomic, and phenotypic data, was used to identify candidate genes and pathways in a mouse model of NASH. The causal role of Matrix Gla Protein (MGP) was validated using heterozygous MGP knockout (Mgp(+/-)) mice. The mechanistic role of MGP in transforming growth factor-beta (TGF-beta) signaling was examined in the LX-2 stellate cell line by using a loss of function approach. RESULTS: Local cis-acting regulation of MGP was correlated with fibrosis, suggesting a causal role in NASH, and this was validated using loss of function experiments in 2 models of diet-induced NASH. Using single-cell RNA sequencing, Mgp was found to be primarily expressed in hepatic stellate cells and dendritic cells in mice. Knockdown of MGP expression in stellate LX-2 cells led to a blunted response to TGF-beta stimulation. This was associated with reduced regulatory SMAD phosphorylation and TGF-beta receptor ALK1 expression as well as increased expression of inhibitory SMAD6. Hepatic MGP expression was found to be significantly correlated with the severity of fibrosis in livers of patients with NASH, suggesting relevance to human disease. CONCLUSIONS: MGP regulates liver fibrosis and TGF-beta signaling in hepatic stellate cells and contributes to NASH pathogenesis.

Automated summary

This study identified candidate genes and pathways involved in the pathogenesis of nonalcoholic steatohepatitis (NASH) by integrating genetic, transcriptomic, and phenotypic data. The study found that Matrix Gla Protein (MGP) plays a regulatory role in liver fibrosis and TGF-beta signaling in hepatic stellate cells, contributing to the development of NASH.