PDF(Pubmed)
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.
摘要：
α-酮戊二酸（AKG），三羧酸循环中的关键中间体，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性肝病的主要诱因，AKG对高脂血症诱导的肝脏代谢紊乱的保护作用仍未得到充分的发挥。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及其机制。我们的观察表明，AKG有效缓解肝脏脂质积累，线粒体功能障碍，和P407诱导的高脂血症小鼠的氧化还原稳态的丧失，以及棕榈酸损伤的HepG2细胞和原代肝细胞。机制见解表明，预防作用是通过激活AMPK-PGC-1α/Nrf2途径介导的。总之,我们的研究结果揭示了AKG在改善高脂血症诱导的脂肪肝异常脂质代谢紊乱中的作用和机制。这表明AKG,内源性线粒体营养素，在解决高脂血症诱导的脂肪肝疾病方面具有广阔的潜力。
