Hepatocyte-specific loss of LAP2 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 LAP2 alpha, a nuclear protein that regulates lamin A/C, were previously identified in patients with NAFLD, we sought to determine the role of LAP2 alpha in NAFLD using a mouse genetic model. Hepatocyte-specific Lap2 alpha-knockout (Lap2 alpha((Delta Hep))) mice and littermate controls were fed normal chow or high-fat diet (HFD) for 8 wk or 6 mo. Unexpectedly, male Lap2 alpha((Delta Hep)) mice showed no increase in hepatic steatosis or NASH compared with controls. Rather, Lap2 alpha((Delta Hep)) 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 Lap2 alpha((Delta Hep)) mice, along with concomitant decreases in expression of pro-inflammatory and pro-fibrotic genes. These data indicate that hepatocyte-specific Lap2 alpha deletion protects against hepatic steatosis and NASH in mice and raise the possibility that LAP2 alpha could become a potential therapeutic target in human NASH.