NLRP6 overexpression improves nonalcoholic fatty liver disease by promoting lipid oxidation and decomposition in hepatocytes through the AMPK/CPT1A/PGC1A pathway
SHI Qing
RAN Suye
SONG Lingyu
YANG Hong
WANG Wenjuan
LIU Hanlin
LIU Qi
Abstract：Objective 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.Conclusion NLRP6 overexpression promotes lipid oxidation and decomposition through AMPK/CPT1A/PGC1A to alleviate lipid deposition in hepatocytes.
Keywords：non-alcoholic fatty liver diseaseNLRP6AMPKfatty acid oxidation
Publication Date：2025-01-19
Online Publishing Date：2025-08-15(First online date of this platform, not the publication date of the document)
Pages：8( 118-125 )