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

There 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 Lap2α-knockout (Lap2α^(ΔHep)) mice and littermate controls were fed normal chow or high-fat diet (HFD) for 8 wk or 6 mo. Unexpectedly, male Lap2α^(ΔHep) mice showed no increase in hepatic steatosis or NASH compared with controls. Rather, Lap2α^(ΔHep) mice demonstrated reduced hepatic steatosis, with decreased NASH and fibrosis after long-term HFD. Accordingly, pro-steatotic genes including Cidea, Mogat1, and Cd36 were downregulated in Lap2α^(ΔHep) mice, along with concomitant decreases in expression of pro-inflammatory and pro-fibrotic genes. These data indicate that hepatocyte-specific Lap2α deletion protects against hepatic steatosis and NASH in mice and raise the possibility that LAP2α could become a potential therapeutic target in human NASH.NEW & NOTEWORTHY The nuclear envelope and lamina regulate lipid metabolism and susceptibility to nonalcoholic steatohepatitis (NASH), but the role of the nuclear lamin-binding protein LAP2α in NASH has not been explored. Our data demonstrate that hepatocyte-specific loss of LAP2α protects against diet-induced hepatic steatosis, NASH, and fibrosis in male mice, with downregulation of pro-steatotic, pro-inflammatory, and pro-fibrotic lamin-regulated genes. These findings suggest that targeting LAP2α could have future potential as a novel therapeutic avenue in NASH.