Chlorogenic acid promotes liver regeneration and repair after acetaminophen-induced liver injury via alleviating oxidative stress and enhancing fatty acid β-oxidation by activating Nrf2.

Abstract

Acetaminophen (ACM)-induced hepatotoxicity involves an acute injury phase followed by a recovery phase. Although N-acetylcysteine (NAC) is widely used clinically to mitigate ACM-caused hepatotoxicity during the initial injury phase, effective therapeutic strategies to promote liver regeneration (LR) during the recovery phase remain unavailable. Chlorogenic acid (CGA), abundantly present in dietary sources, has been shown to exert significant hepatoprotective effects. This study reported that CGA not only promoted LR in mice following ACM (300 mg kg^-1) intoxication (p < 0.05) but also significantly elevated the survival rate of mice treated with a lethal dose (500 mg kg^-1) of ACM, increasing survival from approximately 9% to 45%. Mechanistically, CGA alleviated oxidative liver damage by activating nuclear factor erythroid 2-related factor 2 (Nrf2) and facilitated energy supply for LR via enhancing fatty acid β-oxidation mediated by peroxisome proliferator-activated receptor α (PPARα). Genetic Nrf2 knockout (Nrf2^-/-) and pharmacological inhibition of PPARα (using GW6471) confirmed the critical roles of both Nrf2 and PPARα in this process. Further analysis revealed that the CGA-induced Nrf2 activation upregulated the expression of peroxisome proliferator-activated receptor gamma, coactivator 1-alpha (PGC-1α), a key coactivator of PPARα. Collectively, CGA promoted LR following ACM intoxication by alleviating hepatic oxidative stress via activating Nrf2. Additionally, Nrf2 activation triggered the expression of PGC-1α, which further strengthened PPARα-mediated fatty acid β-oxidation, thereby supplying sufficient energy for CGA-promoted LR following ACM intoxication. These findings highlight CGA's hepatoprotective effects and suggest it as a promising dietary supplement for promoting LR following toxic injury.