The Effect Of FGF21on Acetaminophen-induced Acute Liver Failure In Mice

Acetaminophen (APAP) is a safe analgesic and antipyretic drug when used attherapeutic doses. However, an overdose of APAP has serious side effects. APAPoverdose leads to necrosis of liver, and even evolve into acute liver failure (ALF).APAP overdose has become the most common cause of ALF in most Westerncountries. At present, N-acetylcysteine (NAC) is mainly used in APAP-induced ALF.However, treatment with NAC has great limitations. It has therapeutic effects atabout1hour after APAP overdose and therapeutic effects gradually disappear withtime. Thus, it is necessary to find other therapeutic drugs in APAP-induced ALF.Fibroblast growth factor21(FGF21) is a recently discovered member of theFGF19subfamily. FGF21can regulate the metabolism of lipid and carbohydrate. Itattracted more and more attention for its antihyperglycemic effects withnon-insulin-dependent. Recent studies also demonstrated that FGF21showedprotective effects in a variety of acute stimulus conditions demonstrating that FGF21may serve as a protective factor. In present study, we studied the role of FGF21inAPAP-induced ALF by comparing the differences of liver injury in loss of functionand gain of function conditions.Mice were fasted for12hours and intraperitoneally injected with400mg/kgAPAP to induce ALF. The alteration of endogenous FGF21expression wasexamined after APAP treatment. The differences of liver injury between wild type(WT) mice and FGF21knock-out (KO) mice were compared. Furthermore, theeffects of exogenous FGF21proteins to APAP-induced ALF were also examined.Enzyme-linked immunosorbent assay (ELISA), quantitative-polymerase chain reaction (Q-PCR), western blotting (WB) and other biochemical and morphologicalmethods were used for comprehensive analyses. Our results showed that serum andhepatic FGF21levels were rapidly and robustly increased at early stage. Theelevated FGF21restored to basal levels with time. The degree of liver injury wasmore serious in FGF21KO mice than in WT mice after APAP treatment. Hepaticchemotactic factors and intercellular adhesion molecules that associated withexacerbating liver injury were higher in FGF21KO mice than in the correspondingWT mice. On the other hand, many protective factors were reduced in FGF21KOmice. In APAP-treated mice, exogenous FGF21protein significantly suppressed theincrease of serum transaminases and reduced the necrosis of liver. In APAP-inducedALF, neutrophil infiltration is an important cause that leads to further liver injury.Results showed exogenous FGF21protein reduced multiple parameters of neutrophilinfiltration including chemokines and intracellular adhesion molecules.The present study demonstrated that endogenous FGF21expression wasinduced in drug-induced ALF and the deletion of FGF21aggravated liver injury.Exogenous FGF21protein administration reduced liver injury and the protectiveeffects of FGF21may be mediated by decreasing neutrophil infiltration.