Kaempferol protects mice from d-GalN/LPS-induced acute liver failure by regulating the ER stress-Grp78-CHOP signaling pathway.

Kaempferol is a flavonoid compound that has many functions, such as anti-inflammation and antioxidation. Acute liver failure (ALF) is a life-threatening illness accompanied by serious inflammation and extensive hepatocyte apoptosis. The aim of this study was to examine the therapeutic potential of kaempferol and its mechanism in ALF. In a murine ALF model induced by d-galactosamine (d-GalN, 700 mg/kg) / lipopolysaccharide (LPS, 10 μg/kg), mice were pretreated with kaempferol at 2 h before d-GalN/LPS administration and then sacrificed 6 h after d-GalN/LPS injection. Lethality, liver damage, endoplasmic reticulum(ER) stress, hepatocyte viability and apoptosis were evaluated. Whether pretreatment of kaempferol protected hepatocytes from ER stress-induced apoptosis was detected in vitro. Pretreatment of kaempferol decreased lethality, prolonged the survival time and significantly protected against liver injury, which was indicated by decreased transaminase levels and the well-preserved liver structure. The protective effect of kaempferol on the ALF mouse model was achieved by inhibiting hepatocyte apoptosis. Moreover, pretreatment of kaempferol increased the expression of glucose-regulated/binding immunoglobulin protein 78 (Grp78), decreased the expression of C/EBP-homologous protein (CHOP), and protected hepatocytes from ER stress-induced apoptosis in vitro. Our results showed that pretreatment of Grp78 siRNA partially negated the hepatic protection from kaempferol and reversed the inhibition of CHOP protein expression in d-GalN/LPS-induced ALF mice. In conclusion, kaempferol inhibits hepatocyte apoptosis to protect mice from liver failure by regulating the ER stress-Grp78-CHOP signaling pathway. Therefore, kaempferol may be used to treat ALF.

Wang H ，Chen L ，Zhang X ，Xu L ，Xie B ，Shi H ，Duan Z ，Zhang H ，Ren F ... -  《-》

Peroxisome proliferator-activated receptor alpha acts as a mediator of endoplasmic reticulum stress-induced hepatocyte apoptosis in acute liver failure.

Peroxisome proliferator-activated receptor α (PPARα) is a key regulator to ameliorate liver injury in cases of acute liver failure (ALF). However, its regulatory mechanisms remain largely undetermined. Endoplasmic reticulum stress (ER stress) plays an important role in a number of liver diseases. This study aimed to investigate whether PPARα activation inhibits ER stress-induced hepatocyte apoptosis, thereby protecting against ALF. In a murine model of D-galactosamine (D-GalN)- and lipopolysaccharide (LPS)-induced ALF, Wy-14643 was administered to activate PPARα, and 4-phenylbutyric acid (4-PBA) was administered to attenuate ER stress. PPARα activation ameliorated liver injury, because pre-administration of its specific inducer, Wy-14643, reduced the serum aminotransferase levels and preserved liver architecture compared with that of controls. The protective effect of PPARα activation resulted from the suppression of ER stress-induced hepatocyte apoptosis. Indeed, (1) PPARα activation decreased the expression of glucose-regulated protein 78 (Grp78), Grp94 and C/EBP-homologous protein (CHOP) in vivo; (2) the liver protection by 4-PBA resulted from the induction of PPARα expression, as 4-PBA pre-treatment promoted upregulation of PPARα, and inhibition of PPARα by small interfering RNA (siRNA) treatment reversed liver protection and increased hepatocyte apoptosis; (3) in vitro PPARα activation by Wy-14643 decreased hepatocyte apoptosis induced by severe ER stress, and PPARα inhibition by siRNA treatment decreased the hepatocyte survival induced by mild ER stress. Here, we demonstrate that PPARα activation contributes to liver protection and decreases hepatocyte apoptosis in ALF, particularly through regulating ER stress. Therefore, targeting PPARα could be a potential therapeutic strategy to ameliorate ALF.

Zhang L ，Ren F ，Zhang X ，Wang X ，Shi H ，Zhou L ，Zheng S ，Chen Y ，Chen D ，Li L ，Zhao C ，Duan Z ... -  《-》

Inhibition of glycogen synthase kinase 3β ameliorates D-GalN/LPS-induced liver injury by reducing endoplasmic reticulum stress-triggered apoptosis.

Chen L ，Ren F ，Zhang H ，Wen T ，Piao Z ，Zhou L ，Zheng S ，Zhang J ，Chen Y ，Han Y ，Duan Z ，Ma Y ... -  《PLoS One》

Protective Role of 4-Octyl Itaconate in Murine LPS/D-GalN-Induced Acute Liver Failure via Inhibiting Inflammation, Oxidative Stress, and Apoptosis.

Oxidative stress, inflammation, and apoptosis are crucial in the pathogenesis of acute liver failure (ALF). 4-Octyl itaconate (OI) showed antioxidative and anti-inflammatory properties in many disease models. However, its role in lipopolysaccharide- (LPS-)/D-galactosamine- (D-GalN-) induced ALF is still not investigated. Here, we established an ALF murine model induced by LPS/D-GalN administration. And we found that OI improved survival rate in the murine ALF model. Our results also showed that OI alleviated LPS/D-GalN-induced hepatic histopathological injury and reduced the serum activities of alanine transaminase and aspartate transaminase. Moreover, OI reduced serum levels of proinflammatory cytokines such as monocyte chemotactic protein-1, tumor necrosis factors-α, and interlukin-6. Additionally, OI mitigated oxidative stress and alleviated lipid peroxidation in a murine model of ALF. This was evaluated by a reduction of thiobarbituric acid reactive substances (TBARS) in liver tissues. In addition, OI increased the ratio of reduced glutathione/oxidized glutathione and the activities of antioxidant enzymes including catalase and superoxide dismutase. Moreover, the apoptosis of hepatocytes in the liver was inhibited by OI. Furthermore, we found that OI inhibited LPS-induced nuclear translocation and activation of factor-kappa B (NF-κB) p65 in macrophages which could be inhibited by OI-induced activation of nuclear factor erythroid-2-related factor (Nrf2) signaling. Additionally, D-GalN-induced reactive oxygen species (ROS) generation and apoptosis in hepatocytes were inhibited by OI-induced activation of Nrf2 signaling. Therefore, the underlying mechanism for OI's protective effect in LPS/D-GalN-induced ALF may be associated with deactivation of NF-κB signaling in macrophages to reduce inflammation and inhibition of ROS-related hepatocyte apoptosis by activating Nrf2. In conclusion, OI showed a protective role in LPS/D-GalN-induced ALF by reducing inflammation, enhancing antioxidant capacity, and inhibiting cell apoptosis.

Li R ，Yang W ，Yin Y ，Zhang P ，Wang Y ，Tao K ... -  《-》

[Role of endoplasmic reticulum stress-mediated glycogen synthase kinase 3β activity in pathogenesis of acute liver failure in mice].

Gao H ，Zhang XY ，Yue LY ，Liu ZY ，Jia NN ，Chen DX ，Duan ZP ，Ren F ... -  《-》