NLRP6 overexpression improves nonalcoholic fatty liver disease by promoting lipid oxidation and decomposition in hepatocytes through the AMPK/CPT1A/PGC1A pathway.
10.12122/j.issn.1673-4254.2025.01.15
- Author:
Qing SHI
1
;
Suye RAN
1
;
Lingyu SONG
1
;
Hong YANG
1
;
Wenjuan WANG
1
;
Hanlin LIU
1
;
Qi LIU
1
Author Information
1. Department of Gastroenterology, Affiliated Hospital of Guizhou Medical University, Guiyang 550000, China.
- Publication Type:Journal Article
- Keywords:
AMPK;
NLRP6;
fatty acid oxidation;
non-alcoholic fatty liver disease
- MeSH:
Non-alcoholic Fatty Liver Disease/metabolism*;
Animals;
Hepatocytes/metabolism*;
Lipid Metabolism;
Mice;
Humans;
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha;
AMP-Activated Protein Kinases/metabolism*;
Carnitine O-Palmitoyltransferase/metabolism*;
Diet, High-Fat;
Male;
Mice, Inbred C57BL;
Signal Transduction
- From:
Journal of Southern Medical University
2025;45(1):118-125
- CountryChina
- Language:English
-
Abstract:
OBJECTIVES:To investigate the regulatory role of nucleotide-bound oligomerized domain-like receptor containing pyrin-domain protein 6 (NLRP6) in liver lipid metabolism and non-alcoholic fatty liver disease (NAFLD).
METHODS:Mouse models with high-fat diet (HFD) feeding for 16 weeks (n=6) or with methionine choline-deficient diet (MCD) feeding for 8 weeks (n=6) were examined for the development of NAFLD using HE and oil red O staining, and hepatic expressions of NLRP6 were detected with RT-qPCR, Western blotting, and immunohistochemical staining. Cultured human hepatocytes (LO2 cells) with adenovirus-mediated NLRP6 overexpression or knock-down were treated with palmitic acid (PA) in the presence or absence of compound C (an AMPK inhibitor), and the changes in cellular lipid metabolism were examined by measuring triglyceride, ATP and β-hydroxybutyrate levels and using oil red staining, RT-qPCR, and Western blotting.
RESULTS:HFD and MCD feeding both resulted in the development of NAFLD in mice, which showed significantly decreased NLRP6 expression in the liver. In PA-treated LO2 cells, NLRP6 overexpression significantly decreased cellular TG content and lipid deposition, while NLRP6 knockdown caused the opposite effects. NLRP6 overexpression in PA-treated LO2 cells also increased mRNA and protein expressions of PGC1A and CPT1A, levels of ATP and β-hydroxybutyrate, and the phosphorylation level of AMPK pathway; the oxidative decomposition of lipids induced by Ad-NLRP6 was inhibited by the use of AMPK inhibitors.
CONCLUSIONS:NLRP6 overexpression promotes lipid oxidation and decomposition through AMPK/CPT1A/PGC1A to alleviate lipid deposition in hepatocytes.
