| First Author | Upadhyay KK | Year | 2023 |
| Journal | Am J Physiol Gastrointest Liver Physiol | Volume | 325 |
| Issue | 2 | Pages | G184-G195 |
| PubMed ID | 37366543 | Mgi Jnum | J:362175 |
| Mgi Id | MGI:7785408 | Doi | 10.1152/ajpgi.00214.2022 |
| Citation | Upadhyay KK, et al. (2023) Hepatocyte-specific loss of LAP2alpha protects against diet-induced hepatic steatosis, steatohepatitis, and fibrosis in male mice. Am J Physiol Gastrointest Liver Physiol 325(2):G184-G195 |
| abstractText | 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 LAP2alpha, a nuclear protein that regulates lamin A/C, were previously identified in patients with NAFLD, we sought to determine the role of LAP2alpha in NAFLD using a mouse genetic model. Hepatocyte-specific Lap2alpha-knockout (Lap2alpha((DeltaHep))) mice and littermate controls were fed normal chow or high-fat diet (HFD) for 8 wk or 6 mo. Unexpectedly, male Lap2alpha((DeltaHep)) mice showed no increase in hepatic steatosis or NASH compared with controls. Rather, Lap2alpha((DeltaHep)) 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 Lap2alpha((DeltaHep)) mice, along with concomitant decreases in expression of pro-inflammatory and pro-fibrotic genes. These data indicate that hepatocyte-specific Lap2alpha deletion protects against hepatic steatosis and NASH in mice and raise the possibility that LAP2alpha 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 LAP2alpha in NASH has not been explored. Our data demonstrate that hepatocyte-specific loss of LAP2alpha 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 LAP2alpha could have future potential as a novel therapeutic avenue in NASH. |
