The Protective Role And Mechanism Of Pgc1α In Nonalcoholic Steatohepatitis

Aim:Peroxisome proliferator-activated receptor gamma,coactivator 1 alpha(PGC1α),a transcriptional coactivator that mediates adipose metabolism and mitochondrial biogenesis.However,its role in hepatic steatosis and progression to steatohepatitis remains elusive.In this study we aimed to investigate the protective effects and underlying mechanisms of PGC1α on development of nonalcoholic steatohepatitis.Materials and Methods:For evaluating the effect of PGC1α on hepatic steatosis,eight-to ten-week-old Liv hepatocyte-specific PGC1α overexpression(LivPGC1α)mice and wild type mice were fed with high fat diet(HFD)for 8 weeks,respectively.For further evaluating the effect of PGC1α on nonalcoholic steatohepatitis(NASH),PGC1α mice and wild type mice were fed with methionine-choline deficient(MCD)diet for 5 weeks,we further explore the role of PGC1α on hepatic inflammatory infiltration,apoptosis,oxidative stress and fibrosis in MCD diet induced NASH model.Furthermore,we added nicotinamide adenine denucleotide(NAD+)precursor nicotinamide mononucleotide(NMN)to observe its role in hepatic steatosis in MCD diet induced NASH model.In addition,molecμlar biological methods such as qRT-PCR,WB and flow cytometry were used to analyze the regμlating effect of PGC1α on NAD+ biosynthesis.Meanwhile,in NAFLD patients,the expression of PGC1-NAD+ pathway was further evaluated.Resμlts:We demonstrated that Hepatic PGC1α overexpression significantly ameliorated hepatic steatosis induced by HFD.Hepatic PGC1α overexpression significantly alleviated hepatic inflammatory infiltration,apoptosis,oxidative stress and NF-kb activation in MCD diet induced NASH models.Hepatic PGC1α can markedly upregμlate hepatic NAD+ biosynthesis,mitochondrial DNA content,mitochondrial fatty acid oxidation related protein PPARa and its downstream molecμles in MCD diet induced NASH models.Furthermore,NAD+ repletion via its precursor β-NMN significantly reduced hepatic triglyceride content,oxidative stress,and liver enzyme in mice fed MCD.Meanwhile,in NAFLD patients,the expression of PGC1 and NAD+were markedly decreased.Conclusions:These findings indicate that hepatic-specific overexpression of PGC1α exerts a beneficial role in the regμlation of hepatic lipid homeostasis,inflammatory infiltration,apoptosis,oxidative stress and fibrosis.that pharmacological activation of PGC1α-NAD+ may be important for the prevention of nonalcoholic steatohepatitis.