Hepatocyte-specific loss of LAP2α protects against diet-induced hepatic steatosis and steatohepatitis in male mice

Abstract

AbstractThere is increasing evidence for the importance of the nuclear envelope in lipid metabolism, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). Human mutations in LMNA, encoding A-type nuclear lamins, cause early-onset insulin resistance and NASH, while hepatocyte-specific deletion of Lmna predisposes to NASH with fibrosis in male mice. Given that variants in the gene encoding LAP2α, a nuclear protein that regulates lamin A/C, were previously identified in patients with NAFLD, we sought to determine the role of LAP2α in NAFLD using a mouse genetic model. Hepatocyte-specific Lap2a-knockout (Lap2α(ΔHep)) mice and littermate controls were fed normal chow or high-fat diet (HFD) for 8 weeks or 6 months. In contrast to what was observed with hepatocyte-specific Lmna deletion, male Lap2a(ΔHep) mice showed no increase in hepatic steatosis or NASH compared to controls. Rather, Lap2a(ΔHep) mice demonstrated reduced hepatic steatosis, particularly after long-term HFD, with decreased susceptibility to diet-induced NASH. Accordingly, whereas pro-steatotic genes Cidea, Mogat1, and Cd36 were upregulated in Lmnα-KO mice, they were downregulated in Lap2α(ΔHep) mice, and there was a trend toward decreases in pro-inflammatory and pro-fibrotic genes. These data indicate that hepatocyte-specific Lap2a deletion protects against hepatic steatosis and NASH in mice; therefore, LAP2α might represent a potential therapeutic target in human NASH.Brief SummaryLoss of LAP2α in mouse hepatocytes protected against diet-induced hepatic steatosis and NASH.