The Role Of NAMPT In Acetaminophen-induced Acute Liver Injury

Background:Acetaminophen(APAP)is an antipyretic and analgesic drug commonly used in clinical,but overdose of APAP can induce acute liver injury(ALI),acute hepatic failure(ALF),or even death,which is an important subject of public health.A large number of studies have confirmed that the principal pathogenesis of ALI caused by overdose of APAP includes energy metabolism disorder,oxidative stress,and inflammatory reaction.The inflammatory response is triggered by energy metabolism impairment and hepatic oxidative stress,which in turn aggravates liver damage and forms a vicious cycle.There are many signal transduction pathways involved in this process,including some key molecules and inflammatory factors,such as nuclear factor kappa B(NF-?B),interleukin-6(IL-6),nterleukin-1?(IL-1?),tumor necrosis factors-?(TNF-?),etc.Although remarkable progress has been made in studying the role of inflammatory responses in ALI,many problems remain to be elucidated.Therefore,it is of theoretical value and practical significance to explore the pathogenesis of ALI caused by APAP from the perspective of inflammation,and then to find new targets for drug intervention.Nicotinamide phosphoribosyl transferase(NAMPT)is the rate-limiting enzyme that catalyzes the production of nicotinamide mononucleotide(NMN)from nicotinamide(NAM).NMN further produces nicotinamide adenine dinucleotide.Nicotinamide adenine dinucleotide(NAD),an oxidized form of NAD~+,can regulate the activity of many enzymes,such as silent information regulator 1(SIRT1).SIRT1 is an important NAD~+dependent deacetylase which plays pivotal roles in many life processes,such as inflammation,apoptosis and metabolism.In addition to regulating the metabolism of NAD,NAMPT is also considered as an inflammatory factor and is involved in the inflammatory process of vascular injury,atherosclerosis,endothelial dysfunction and so on.Therefore,whether NAMPT plays a role in APAP induced inflammatory response is worthy of further study.Objective:To investigate the role and preliminary mechanism of NAMPT in acetaminophen-induced acute liver injury.Methods:In this study,we first attempted to establish APAP-induced ALI model in C57BL/6 mice,and detect biochemical markers and pathological changes related to liver injury.Then,the protein expression of NAMPT in ALI was studied.Furthermore,pretreatment with the NAMPT specific inhibitor FK866 was performed to observe its protective effect and its influence on inflammatory factors and key molecules involved in signal transduction pathways,which is order to explore the role and preliminary mechanism of NAMPT in the ALI induced by APAP.Results:The APAP induced ALI model was successfully established on C57BL/6 mice.When compared with the normal control group,the NAMPT content in serum and liver homogenate of mice in APAP model group was highly expressed.Compared with the APAP model group,the serum levels of NAMPT in the serum and liver homogenate of the Fk866 pretreatment group decreased.At the same time,serum ALT and AST activity decreased,and the degree of liver pathological damage was significantly reduced,suggesting that FK866 has a good protective effect on the liver.Further test results showed that the concentrations of inflammatory cytokines IL-6,IL-1?,and TNF-?in the serum of the FK866 pretreatment group decreased,the NAD~+content in the liver homogenate decreased,the expression of SIRT1 in the liver increased,and the expression of NF-?B was decreased.These results suggest that inhibiting the expression of NAMPT in mice can reduce the inflammatory reaction of the liver,and its mechanism may be related to the NF-?B/SIRT1 signaling pathway.Conclusion:NAMPT is involved in the inflammatory response within ALI induced by APAP,and inhibiting its expression has anti-ALI effect.