SEMA7AR148W mutation promotes lipid accumulation and NAFLD progression via increased localization on the hepatocyte surface

Genetic polymorphisms are associated with the development of nonalcoholic fatty liver disease (NAFLD). Semaphorin7a (Sema7a) deficiency in mouse peritoneal macrophages reduces fatty acid (FA) oxidation. Here, we identified 17 individuals with SEMA7A heterozygous mutations in 470 patients with biopsy-proven NAFLD. SEMA7A heterozygous mutations increased susceptibility to NAFLD, steatosis severity, and NAFLD activity scores in humans and mice. The Sema7a(R145W) mutation (equivalent to human SEMA7AR(148W)) significantly induced small lipid droplet accumulation in mouse livers compared with WT mouse livers. Mechanistically, the Sema7aR(145W) mutation increased N-glycosylated Sema7a and its receptor integrin beta 1 proteins in the cell membranes of hepatocytes. Furthermore, Sema7aR(145W) mutation enhanced its protein interaction with integrin beta 1 and PKC-alpha and increased PKC-alpha phosphorylation, which were both abrogated by integrin beta 1 silencing. Induction of PKC alpha_WT, but not PKC alpha_dominant negative, overexpression induced transcriptional factors Srebp1, Chrebp, and Lxr expression and their downstream Acc1, Fasn, and Cd36 expression in primary mouse hepatocytes. Collectively, our findings demonstrate that the SEMA7AR(148W) mutation is a potentially new strong genetic determinant of NAFLD and promotes intrahepatic lipid accumulation and NAFLD in mice by enhancing PKC-alpha-stimulated FA and triglyceride synthesis and FA uptake. The inhibition of hepatic PKC-alpha signaling may lead to novel NAFLD therapies.

Automated summary

The SEMA7AR(148W) mutation is identified as a potentially strong genetic determinant of NAFLD, promoting intrahepatic lipid accumulation and NAFLD by enhancing PKC-alpha-stimulated fatty acid and triglyceride synthesis and fatty acid uptake.