LRRK2 Regulates CPT1A to Promote β-Oxidation in HepG2 Cells

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.

Tri-Herbal Medicine Divya Sarva-Kalp-Kwath (Livogrit) Regulates Fatty Acid-Induced Steatosis in Human HepG2 Cells through Inhibition of Intracellular Triglycerides and Extracellular Glycerol Levels

“…Prolonged enhancement of CPT1A activity can lead to increased mitochondrial energy metabolism leading to heightened reactive oxygen species generation and causing cellular damage and apoptosis [60]. Whereas, a decrease in CPT1A expression can lead to reduced β-oxidation in liver and could contribute to fatty acid accumulation and inflammation in hepatocytes [61]. Thus, our study could show that the reduced levels of intracellular lipids in both the pretreated and concurrently treated HepG2 cells and primary rat hepatocytes with SKK were through the modulation of the FFA-stimulated steatosis related transcription factors (SREBP1c and C/EBPα), and associated lipogenic gene (FAS), which in turn also normalized the fatty acid transporter (CPT1A) gene expression levels responsible for the transport of fatty acids for mitochondrial energy metabolism.…”

The HSF1-CPT1a Pathway Is Differentially Regulated in NAFLD Progression

“…CPT1a-overexpressing mice were protected against obesity-induced weight gain, obesity-induced insulin resistance, and hepatic steatosis [ 29 , 30 ]. Despite the plethora of reports showing upregulation in cellular and animal models, the exact upstream events that lead to increased expression of CPT1a are unclear [ 31 ]. A recent report indicated that the expression of the gene is regulated by methylation and by binding of factors such as C/EBPbeta, PPARalpha, PGC1alpha, and BAF60a to the gene [ 32 ].…”

LRRK2 and Lipid Pathways: Implications for Parkinson’s Disease

“…The effect on oxidation appears to be through LRRK2 regulation of the mitochondrial fatty acid transporter carnitine palmitoyltransferase 1A and the β-oxidation proteins peroxisome proliferator-activated receptor α and AMP-activated protein kinase. This suggests that LRRK2 plays a role in fatty acid catabolism [ 89 ]. In a recent untargeted lipidomics study of LRRK2 mutation carriers, serum lipids significantly discriminating LRRK2 G2019S mutation carriers from non-carriers belonged to pathways related to energy production, including mitochondrial oxidative phosphorylation (acylcarnitine, diacylglycerol and triacylglycerol species), glycerolipid metabolism (diacylglycerol, monogalactosyldiacylglycerol and triacylglycerol species) and retrograde endocannabinoid signaling to modulate mitochondrial respiration (phosphatidylcholine, phosphatidylethanolamine and diacylglycerol species) [ 26 ].…”