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.

中文翻译：

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α-酮戊二酸通过激活 AMPK-pgc-1α/Nrf2 通路预防高脂血症诱导的脂肪肝线粒体功能障碍和氧化应激


α-酮戊二酸 (AKG) 是三羧酸循环中的重要中间体，已被证明可以减轻高脂血症引起的血脂异常和内皮损伤。虽然高脂血症是非酒精性脂肪肝的主要诱因，但 AKG 对高脂血症引起的肝脏代谢紊乱的保护作用仍待探索。本研究旨在探讨AKG对急性高脂血症引起的肝脏脂质代谢紊乱的潜在保护作用和机制。我们的观察表明，AKG 可有效缓解 P407 诱导的高脂血症小鼠以及棕榈酸酯损伤的 HepG2 细胞和原代肝细胞中的肝脏脂质积累、线粒体功能障碍和氧化还原稳态丧失。机制研究表明，预防作用是通过激活 AMPK-PGC-1α/Nrf2 通路介导的。总之，我们的研究结果揭示了 AKG 在改善高脂血症诱发的脂肪肝异常脂质代谢紊乱中的作用和机制，表明 AKG 作为一种内源性线粒体营养素，在解决高脂血症诱发的脂肪肝疾病方面具有广阔的潜力。