LRRK2 Regulates CPT1A to Promote β-Oxidation in HepG2 Cells.

Chiao-Wei Lin,Harry John Mersmann,Yuan-Yu Lin,Shih-Torng Ding,Yu-Ju Peng

doi:10.3390/molecules25184122

Abstract

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.

Highlights

Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease with a global prevalence [1]
The mRNA expression of Leucine-rich repeat kinase 2 (LRRK2) was decreased (p < 0.05) in non-alcoholic fatty liver disease (NAFLD) livers compared to livers of the control group by real-time PCR (Figure 1d)
The LRRK2 protein was lower (p < 0.05) in the NAFLD livers compared to the control group (Figure 1e,f)

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease with a global prevalence [1]. NAFLD is caused by excess fat accumulation in livers [2]. About 20–25% of NAFLD patients progress to non-alcoholic steatohepatitis (NASH), a severe form of NAFLD with inflammation [3]. One of the primary risk factors for NAFLD [1,2,5], leads to the efflux of free fatty acids from adipose tissues into circulation [6,7] resulting in the influx of free fatty acids into other organs, such as liver [8]. Palmitic acid (PA, 16:0), a fatty acid abundant in plasma [9], is increased in the plasma of NAFLD patients [10,11]

Methods

Results

Conclusion