Alpha Ketoglutaric Acid attenuates LPS Induced Inflammatory Response by Inhibiting the PKCε/MAPK/P65 Signaling Pathway and Inhibit Oxidative Stress in Kupffer Cells.

The inflammatory response is crucial in the progression of various liver diseases. Many diseases are linked with inflammation, such as ischemia and reperfusion injury, nonalcoholic steatohepatitis (NASH) and hepatic fibrosis. Research indicates that αKG attenuates NASH. However, the protective effect of αKG on KCs cell inflammation and its mechanism remain unclear. This study aimed to explore the role and mechanism of αKG in LPS-induced inflammation. The inflammatory damage model of KCs was induced by LPS. The study found that αKG supplementation significantly decreased inflammatory and antioxidant indexes in the LPS group, with a notable reduction in LPS-induced inflammation-related factors (P < 0.05). iNOS and COX2 are also used as indicators of macrophage inflammation, and αKG significantly alleviates LPS induced iNOS and COX2 levels (P < 0.05). Further detection of mitochondrial function and oxidative stress indexes showed that αKG supplementation significantly restored mitochondrial damage caused by LPS, inhibited ROS production, restored mitochondrial function, and improved cellular antioxidant capacity (P < 0.05). Finally, it was found that LPS treatment significantly promoted the activation of PKCε/MAPK/P65 signaling pathway, and αKG supplementation significantly inhibited the activation of signaling pathway and alleviated the pro-inflammatory effect of LPS (P < 0.05). The study demonstrated that αKG enhances the anti-inflammatory effects of KCs by decreasing ROS production and inhibiting the PKCε/MAPK/P65 signaling pathway. This is helpful for development the αKG related anti-inflammation drugs to relieving the liver inflammatory response.