Hepatic NAD^+ deficiency as a therapeutic target for NAFLD in aging

摘要

OBJECTIVE Aging is an important risk factor of nonalcoholic fatty liver disease(NAFLD).Here,we investigated whether the deficiency of nicotinamide adenine dinucleotide(NAD+),a ubiquitous coenzyme,links aging with NAFLD.METHODS Hepatic NAD+concentration,together with the protein levels of nicotinamide phosphoribosyltransferase(NAMPT)and several other critical enzymes regulating NAD+biosynthesis,were compared between middle-aged and aged mice or patients.The influences of NAD+decline on the steatosis and steatohepatitis was evaluated in wild-type(WT)and H247A dominant-negative enzymatic-dead NAMPT transgenic mice(DN-NAMPT)under normal and high-fat diet(HFD).RESULTS Hepatic NAD+level decreased in aged mice and people.NAMPT-controlled NAD+salvage,but not de novo biosynthesis pathway,was compromised in liver of elderly mice and human.Under normal chow,middle-age DN-NAMPT mice displayed systemic NAD+reduction,and had moderate NAFLD phenotypes,including lipid accumulation,enhanced oxidative stress,triggered inflammation and impaired insulin sensitivity in liver.Allthese NAFLD phenotypes,especial y the pro-inflammatory factors release,Kupffer cell accumulation,monocytes infiltration,NLRP3 inflammasome pathway,and hepatic fibrosis(Masson’s staining and a-SMA staining),were further deteriorated under HFD challenge.Orally administration of nicotinamide riboside,a natural NAD+precursor,completely corrected these NAFLD phenotypes induced by NAD+deficiency alone or HFD,whereas adenovirusmediated SIRT1 overexpression only partially rescued these phenotypes.CONCLUSION These results provide the first evidence that aging-associated NAD+deficiency is a critical risk factor for NAFLD,and suggest that supplement of NAD+substrates may be a promising therapeutic strategy to prevent and treat NAFLD.