尼克酰胺核糖激活DRP1介导线粒体裂变减轻酒精性脂肪肝的机制OA

Objective To elucidate the role and molecular mechanism underlying dynamin-related protein 1(DRP1)-mediated mitochondrial fission in the alleviation of alcoholic fatty liver(AFL)by nicotinamide riboside(NR).Methods An AFL mouse model was constructed via the standard Gao-Binge(National Institute on Alco-hol Abuse and Alcoholism,NIAAA)protocol,after which NR intervention was administered.Hepatic injury and mitochondrial morphology were subsequently evaluated.For the in vitro experiments,an AFL cellular model was established in AML-12 hepatocytes via co-treatment with ethanol and palmitic acid.To detect mitochondrial mor-phology,mitochondrial membrane potential and DRP1 activity in AML-12 cells,we adopted MitoTracker staining,JC-10 staining,and a combined approach of Western blotting,co-immunoprecipitation and cellular immunofluores-cence for each detection item respectively.To confirm the functional role of DRP1,pharmacological inhibition of DRP1 was performed using Mdivi-1.Results In vivo experiments demonstrated that NR significantly ameliorated alcohol-induced liver injury and inhibited the formation of megamitochondria.Mechanistic investigations revealed that alcohol exposure reduced DRP1 expression,disrupted its phosphorylation homeostasis,impaired its mitochon-drial translocation,and attenuated the binding interaction between DRP1 and mitochondrial fission factor(MFF),a resident receptor on the mitochondrial outer membrane.Notably,NR supplementation effectively reversed these pathological alterations.Furthermore,the hepatoprotective effect of NR was nearly completely abrogated following Mdivi-1,a pharmacological inhibition of DRP1.Conclusion NR alleviates AFL by activating DRP1-mediated mitochondrial fission to maintain mitochondrial dynamic homeostasis,indicating that DRP1 serves as a key potential target for NR in the prevention and treatment of AFL.