Aldehyde dehydrogenase 2 activation ameliorates CCl4 -induced chronic liver fibrosis in mice by up-regulating Nrf2/HO-1 antioxidant pathway.

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is critical in the pathogenesis of alcoholic liver cirrhosis. However, the effect of ALHD2 on liver fibrosis remains to be further elucidated. This study aimed to demonstrate whether ALDH2 regulates carbon tetrachloride (CCl4 )-induced liver fibrosis and to investigate the efficacy of Alda-1, a specific activator of ALDH2, on attenuating liver fibrosis. ALDH2 expression was increased after chronic CCl4 exposure. ALDH2 deficiency accentuated CCl4 -induced liver fibrosis in mice, accompanied by increased expression of collagen 1α1, α-SMA and TIMP-1. Moreover, ALDH2 knockout triggered more ROS generation, hepatocyte apoptosis and impaired mitophagy after CCl4 treatment. In cultured HSC-T6 cells, ALDH2 knockdown by transfecting with lentivirus vector increased ROS generation and α-SMA expression in an in vitro hepatocyte fibrosis model using TGF-β1. ALDH2 overexpression by lentivirus or activation by Alda-1 administration partly reversed the effect of TGF-β1, whereas ALDH2 knockdown totally blocked the protective effect of Alda-1. Furthermore, Alda-1 administration protected against liver fibrosis in vivo, which might be mediated through up-regulation of Nrf2/HO-1 cascade and activation of Parkin-related mitophagy. These findings indicate that ALDH2 deficiency aggravated CCl4 -induced hepatic fibrosis through ROS overproduction, increased apoptosis and mitochondrial damage, whereas ALDH2 activation through Alda-1 administration alleviated hepatic fibrosis partly through activation of the Nrf2/HO-1 antioxidant pathway and Parkin-related mitophagy, which indicate ALDH2 as a promising anti-fibrotic target and Alda-1 as a potential therapeutic agent in treating CCl4 -induced liver fibrosis.