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.

Cerebral disorders are largely associated with impaired cellular metabolism, despite the regulatory mechanisms designed to ensure cell viability and adequate brain function. Mechanistic target of rapamycin (mTOR) signaling is one of the most crucial factors in the regulation of energy homeostasis and its imbalance is linked with a variety of neurodegenerative diseases. Recent advances in the metabolic pathways\' modulation indicate the role of α-ketoglutarate (AKG) as a major signaling hub, additionally highlighting its anti-aging and neuroprotective properties, but the mechanisms of its action are not entirely clear. In this review, we analyzed the physiological and pathophysiological aspects of mTOR in the brain. We also discussed AKG\'s multifunctional properties, as well as mTOR/AKG-mediated functional communications in cellular metabolism. Thus, this article provides a broad overview of the mTOR/AKG-mediated signaling pathways, in the context of neurodegeneration and endogenous neuroprotection, with the aim to find novel therapeutic strategies.