Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan.
Department of Animal Science and Technology, National Taiwan University, Taipei 106, Taiwan.
Molecules. 2020 Sep 9;25(18):4122. doi: 10.3390/molecules25184122.
Leucine-rich repeat kinase 2 (LRRK2) is involved in lipid metabolism; however, the role of LRRK2 in lipid metabolism to affect non-alcoholic fatty liver disease (NAFLD) is still unclear. In the mouse model of NAFLD induced by a high-fat diet, we observed that LRRK2 was decreased in livers. In HepG2 cells, exposure to palmitic acid (PA) down-regulated LRRK2. Overexpression and knockdown of LRRK2 in HepG2 cells were performed to further investigate the roles of LRRK2 in lipid metabolism. Our results showed that β-oxidation in HepG2 cells was promoted by LRRK2 overexpression, whereas LRRK2 knockdown inhibited β-oxidation. The critical enzyme of β-oxidation, carnitine palmitoyltransferase 1A (CPT1A), was positively regulated by LRRK2. Our data suggested that the regulation of CPT1A by LRRK2 may be via the activation of AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor α (PPARα). The overexpression of LRRK2 reduced the concentration of a pro-inflammatory cytokine, tumor necrosis factor α (TNFα), induced by PA. The increase in β-oxidation may promote lipid catabolism to suppress inflammation induced by PA. These results indicated that LRRK2 participated in the regulation of β-oxidation and suggested that the decreased LRRK2 may promote inflammation by suppressing β-oxidation in the liver.
富含亮氨酸重复激酶 2（LRRK2）参与脂质代谢；然而，LRRK2 在脂质代谢中影响非酒精性脂肪性肝病（NAFLD）的作用尚不清楚。在高脂肪饮食诱导的 NAFLD 小鼠模型中，我们观察到肝脏中 LRRK2 减少。在 HepG2 细胞中，棕榈酸（PA）暴露下调了 LRRK2。在 HepG2 细胞中过表达和敲低 LRRK2 以进一步研究 LRRK2 在脂质代谢中的作用。我们的结果表明，LRRK2 过表达促进了 HepG2 细胞中的β-氧化，而 LRRK2 敲低抑制了β-氧化。β-氧化的关键酶肉碱棕榈酰转移酶 1A（CPT1A）受 LRRK2 正向调节。我们的数据表明，LRRK2 通过激活 AMP 激活的蛋白激酶（AMPK）和过氧化物酶体增殖物激活受体α（PPARα）来调节 CPT1A。LRRK2 的过表达降低了 PA 诱导的促炎细胞因子肿瘤坏死因子α（TNFα）的浓度。β-氧化的增加可能促进脂质分解代谢，从而抑制 PA 诱导的炎症。这些结果表明 LRRK2 参与了β-氧化的调节，并表明肝脏中 LRRK2 的减少可能通过抑制β-氧化来促进炎症。
