Abstract： Background:Adiponectin is the most abundant adipokines that plays critical roles in the maintenance of energy homeostasis as well as inflammation regulation.The half-life of adiponectin is very short and the small-molecule adiponectin receptor agonist has been synthesized recently.In the present study,the potential roles of AdipoRon,an adiponectin receptor agonist,in a mouse model of lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced acute hepatitis was explored.Methods:BALB/c mice (n =144,male) were divided into three sets.In set 1,32 mice were randomized into four groups:the control group,the AdipoRon group,the LPS/D-Gal group,and the AdipoRon + LPS/D-Gal group.The mice in set 1 were sacrificed after LPS/D-Gal treatment,and the plasma samples were collected for detection of tumor necrosis factor-alpha (TNF-α).In set 2,the 32 mice were also divided into four groups similar to that of set 1.The mice were sacrificed 6 h after LPS/D-Gal injection and plasma samples and liver were collected.In set 3,80 mice (divided into four groups,n =20) were used for survival observation.The survival rate,plasma aminotransferases,histopathological damage were measured and compared between these four groups.Results:AdipoRon suppressed the elevation of plasma aminotransferases (from 2106.3 ± 781.9 to 286.8 ± 133.1 U/L for alanine aminotransferase,P＜ 0.01;from 566.5 ±243.4 to 180.1 ± 153.3 U/L for aspartate aminotransferase,P＜ 0.01),attenuated histopathological damage and improved the survival rate (from 10％ to 60％) in mice with LPS/D-Gal-induced acute hepatitis.Additionally,AdipoRon down-regulated the production of TNF-α (from 328.6 ± 121.2 to 213.4 ± 52.2 pg/mL,P ＜ 0.01),inhibited the activation of caspase-3 (from 2.04-fold to 1.34-fold of the control),caspase-8 (from 2.03-fold to 1.31-fold of the control),and caspase-9 (from 2.14-fold to 1.43-fold of the control),and decreased the level of cleaved caspase-3 (0.28-fold to that of the LPS/D-Gal group).The number of terminal deoxynucleotidyl transferase-mediated nucleotide nick-end labeling-positive apoptotic hepatocytes in LPS/D-Gal-exposed mice also reduced.Conclusions:These data indicated that LPS/D-Gal-induced acute hepatitis was effectively attenuated by the adiponectin receptor agonist AdipoRon,implying that AdipoRon might become a new reagent for treatment of acute hepatitis.