Leucine‐Rich Repeat Kinase 2 Promotes β‐Oxidation via the Regulation of CPT1a in Nonalcoholic Fatty Liver Disease

Abstract

Nonalcoholic steatohepatitis (NASH) occurs in about 30% patients of the nonalcoholic fatty liver disease (NAFLD), and these patients have high risk to liver cirrhosis and liver cancer. However, the etiology of the NASH development in NAFLD patients has not been clearly elucidated. In the NAFLD mice induced by high‐fat diet, we identified that leucine‐rich repeat kinase 2 (LRRK2) was down‐regulated in the livers accompanied with inflammation. Moreover, the treatment of palmitic acid (PA), a fatty acid that induces inflammation, led to down‐regulation of LRRK2 in HepG2 cells. The in vivo and in vitro data suggested the down‐regulation of LRRK2 may be correlated to liver inflammation. In addition, in PA‐treated HepG2 cells, the overexpression of LRRK2 significantly decreased the intracellular level of non‐esterified fatty acids as a result of the up‐regulation of CPT1a, which acts as the rate limiting step of beta‐oxidation. Accumulated studies have demonstrated the increase of CPT1a can enhance the beta‐oxidation to inhibit the PA‐induced inflammation. Interestingly, the overexpression of LRRK2 suppressed the NF‐kB‐mediated pro‐inflammatory pathway and inhibited the secretion of the pro‐inflammatory cytokine TNFa induced by PA treatments. Therefore, our results suggested the anti‐inflammatory effect of LRRK2 may also work through the promotion of beta‐oxidation in the liver. In this study, we firstly observed that LRRK2 was down‐regulated in the livers of NAFLD mice. Furthermore, the overexpression of LRRK2 enhanced the beta‐oxidation and inhibited the inflammation in HepG2 cells. Conversely, the decrease of LRRK2 resulted in the inflammation by suppressing beta‐oxidation in the livers. Therefore, LRRK2 may be a therapy target to improve NAFLD in human.