α-Lipoic Acid Alleviates Non-Alcoholic Fatty Liver Disease by Elevating Chaperone-Mediated Autophagy and Increasing β-Oxidation via AMPK-TFEB Axis

Background: Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disorder associated with impaired lipid metabolism and oxidative stress. As a natural antioxidant and dithiol compound, α-lipoic acid (ALA) may play a beneficial role in modulating hepatic metabolism. This study investigates the potential mechanisms through which ALA may alleviate NAFLD.

Methods: To construct an NAFLD model, NCTC 1469 cells were exposed to oleic acid and palmitic acid (OA/PA) and glucose for 24 h. RT-qPCR, Western blotting, and siRNA analyses were used to examine the effects and mechanisms of ALA. In vivo, C57BL/6J mice were fed a high-fat diet for 11 weeks and treated with ALA (200 mg/kg/day, intragastrical) for 4 weeks to evaluate its impact on NAFLD.

Results: In NCTC 1469 cells exposed to OA/PA and glucose, ALA markedly reduced lipid accumulation by activating TFEB, which in turn promoted fatty acid β-oxidation and chaperone-mediated Autophagy (CMA). Furthermore, ALA activated NRF2-dependent CMA and mitigated oxidative stress. Inhibition of AMPK or silencing of TFEB/NRF2 abolished these effects, indicating the key role of the AMPK-TFEB/NRF2 axis. In HFD-fed mice, ALA alleviated hepatic steatosis, serum lipid abnormalities, and liver injury, consistent with its activation of CMA and β-oxidation and reduction in oxidative stress via this pathway.

Conclusions: ALA synchronously activates CMA, β-oxidation, and antioxidant responses via a unified AMPK pathway to reduce lipid accumulation and oxidative stress, providing a mechanistically integrated therapeutic strategy for NAFLD.

chaperone-mediated autophagy (CMA); non-alcoholic fatty liver disease (NAFLD); nuclear factor-erythroid 2-p45 derived factor 2 (NRF2); transcription factor EB (TFEB); α-lipoic acid (ALA).