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

Abstract

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 LMNA, 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 (HKO) 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 HKO mice showed no increase in hepatic steatosis or NASH compared to controls. Rather, HKO 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 Lmna-KO mice, they were downregulated in HKO mice, as were pro-inflammatory and pro-fibrotic genes. These data indicate that Lap2α deletion enhances hepatoprotective LMNA-mediated regulation of gene expression in mouse hepatocytes; therefore, LAP2α might represent a potential therapeutic target in human NASH.

A common variant that alters SUN1 degradation associates with hepatic steatosis and metabolic traits in multiple cohorts

“…In addition, the identification of this common SUN1 variant associated with NASH, insulin resistance, and metabolic disease puts the nuclear envelope squarely among the subcellular structures with important roles in the pathogenesis of these diseases. Prior work from our group has suggested based on pre-clinical studies that a lamin-associated protein, LAP2α, might be a promising therapeutic target to enhance the hepatoprotective effects of lamin A/C in NASH (Upadhyay et al, 2022); now, this study suggests that SUN1 might also be a potential target, with a common coding variant that may play a functional role in a significant proportion of patients with NASH. This is of particular relevance because it appears quite likely, based on the clinical trial evidence available to date, that combinatorial and patient-targeted therapeutic approaches may be increasingly utilized in the treatment of NASH (Alkhouri et al, 2022).…”