Histidine-alleviated hepatocellular death in response to 4-hydroxynonenal contributes to the protection against high-fat diet-induced liver injury

4-Hydroxynonenal (4-HNE) is a critical lipid peroxidation product induced by oxidative stress that has been implicated in the pathophysiology of non-alcoholic fatty liver disease (NAFLD). We previously reported that histidine ameliorated oxidative stress in both obese women and high-fat diet (HFD)-induced rats. However, the mechanism of histidine against liver injury in NAFLD remains unclear. This study aimed to investigate the effect of histidine supplementation on alleviating HFD-induced liver injury. Histidine relieved both HFD-induced liver injury and 4-HNE-induced hepatotoxicity. Histidine acted partly by inhibiting both c-Jun-N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) pathways in paralle, while the reactive oxygen species-mediated MAPKs axes were also implicated in the protective role of histidine. Histidine reversed 4-HNE-protein adducts formation in both rat liver and hepatocytes. These findings suggest that increased histidine intake may be a potential therapeutic choice for NAFLD.