α-Ketoglutarate prevents hyperlipidemia-induced fatty liver mitochondrial dysfunction and oxidative stress by activating the AMPK-pgc-1α/Nrf2 pathway
Danyu Cheng, Mo Zhang, Yezi Zheng, Min Wang, Yilin Gao, Xudong Wang, Xuyun Liu, Weiqiang Lv, Xin Zeng, Konstantin N. Belosludtsev, Jiacan Su, Lin Zhao, Jiankang Liu
Abstract
α-Ketoglutarate (AKG), a crucial intermediate in the tricarboxylic acid cycle, has been demonstrated to mitigate hyperlipidemia-induced dyslipidemia and endothelial damage. While hyperlipidemia stands as a major trigger for non-alcoholic fatty liver disease, the protection of AKG on hyperlipidemia-induced hepatic metabolic disorders remains underexplored. This study aims to investigate the potential protective effects and mechanisms of AKG against hepatic lipid metabolic disorders caused by acute hyperlipidemia. Our observations indicate that AKG effectively alleviates hepatic lipid accumulation, mitochondrial dysfunction, and loss of redox homeostasis in P407-induced hyperlipidemia mice, as well as in palmitate-injured HepG2 cells and primary hepatocytes. Mechanistic insights reveal that the preventive effects are mediated by activating the AMPK-PGC-1α/Nrf2 pathway. In conclusion, our findings shed light on the role and mechanism of AKG in ameliorating abnormal lipid metabolic disorders in hyperlipidemia-induced fatty liver, suggesting that AKG, an endogenous mitochondrial nutrient, holds promising potential for addressing hyperlipidemia-induced fatty liver conditions. AKG regulates mitochondrial function and redox balance via activating the AMPK-PGC-1α/Nrf2 pathway to prevent hyperlipidemia-induced fatty liver. • AKG prevents hyperlipidemia-induced hepatic lipid metabolic disorders in mice through the AMPK-PGC-1α/Nrf2 pathway.