Alpha-Lipoic Acid: A Preclinical Strategy Against Hepatic Steatosis

In preclinical models of nonalcoholic fatty liver disease, alpha-lipoic acid (ALA) reduced hepatic lipid accumulation and altered hepatocellular lipid handling, with concordant histologic and biochemical changes observed in vitro and in diet-induced mouse models. In treated hepatocytes and high-fat-diet (HFD) mice, ALA engagement of the AMPK–TFEB/NRF2 signaling network correlated with lower hepatic triglyceride content, reduced lipid-droplet staining, and improved serum lipid profiles. These mechanistic data link a nutraceutical intervention to reductions in hepatic lipid burden and support targeted translational follow-up.

ALA activates the AMPK–TFEB axis in hepatocytes and liver tissue, shown by restored AMPK Thr172 phosphorylation and TFEB activation in experimental models. AMPK phosphorylation serves as an energy-sensing trigger that promotes downstream signaling; TFEB then translocates to the nucleus and upregulates lysosomal and lipid-catabolic programs. Downstream induction of PPARα and PGC1α, and the enhancement of lysosomal machinery, connect upstream AMPK activity to increased lipid clearance via TFEB-mediated transcription — a link supported by pathway inhibition and genetic knockdown experiments in the reported work.

Activation of the AMPK–TFEB cascade was associated with increased fatty acid β‑oxidation and enhanced chaperone-mediated autophagy (CMA), together reducing hepatocellular lipid stores. Upregulation of PPARα and PGC1α and markers of mitochondrial fatty acid oxidation were consistent with accelerated fatty-acyl catabolism that lowers intracellular triglyceride pools. Concurrent increases in CMA activity and higher LAMP2A/HSC70 expression likely facilitated selective turnover of lipid-droplet–associated proteins and damaged organelles, improving lipid droplet mobilization and organelle quality control.

ALA’s antioxidant actions were experimentally linked to NRF2 pathway activation: treated hepatocytes showed lower oxidative markers and an augmented antioxidant response. NRF2 induction increased canonical targets such as HO‑1, NQO1, and SOD2 and reduced measures of lipid peroxidation and intracellular ROS. This antioxidant response complements autophagy-driven lipid clearance and provides a reinforcing mechanism for the observed lipid-lowering effects in preclinical settings.

Methods combined complementary in vitro and in vivo approaches: hepatocyte steatosis was induced in a mouse hepatocyte line with oleic/palmitic acid plus high glucose and treated with ALA (in vitro dose reported at 200 µM). Male C57BL/6J mice received a high‑fat diet and oral ALA (reported 200 mg/kg/day) with group sizes of n = 4 per HFD/ALA arm in the animal experiments; these small group sizes limit statistical power and warrant replication in larger cohorts to confirm robustness and dose‑response relationships.

Key Takeaways:

• What’s new: ALA mechanistically activates AMPK–TFEB signaling to synchronize increased β‑oxidation and chaperone‑mediated autophagy, reducing hepatocellular lipid accumulation.
• Who’s affected: Patients with hepatic steatosis/NAFLD and preclinical researchers exploring pathway-directed interventions are the primary audiences for these findings.
• What changes next: Prioritize mechanistic replication, dose‑finding, and safety studies before human efficacy trials to establish translational relevance.