• Liya Chen, Anna L Lang, Gavin D Poff, Wen-Xing Ding, and Juliane I Beier.
• Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY, 40202, USA; Hepatobiology and Toxicology Program, University of Louisville Health Sciences Center, Louisville, KY, 40202, USA; University of Louisville Alcohol Research Center, University of Louisville Health Sciences Center, Louisville, KY, 40202, USA. Electronic address: l0chen26@foxmail.com.
• Redox Biol. 2019 Jun 1; 24: 101205.

AbstractVinyl chloride (VC), an abundant environmental contaminant causes steatohepatitis at high levels, but is considered safe at lower (i.e., sub-OSHA) levels. However, we have previously shown that even lower VC levels exacerbate experimental nonalcoholic fatty liver disease (NAFLD) caused by high-fat diet (HFD). Mitochondrial oxidative injury and subsequent metabolic dysfunction appeared to play key roles in mediating this interaction. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) serves as a key line of defense against endogenous and exogenous reactive aldehydes. The current study therefore tests the hypothesis that allosteric activation of ALDH2 with Alda-1 will protect against VC-enhanced NAFLD. Mice were exposed to low VC concentrations (<1 ppm), or room air for 6 h/day, 5 days/week for 12 weeks, while on HFD or low-fat control diet (LFD). Some mice received Alda-1 (20 mg/kg i.p., 3 × /week) for the last 3 weeks of diet/VC exposure. Indices of liver injury, oxidative stress, metabolic and mitochondrial (dys)function were measured. As observed previously, low-dose VC did not cause liver injury in control mice; while liver injury caused by HFD was enhanced by VC. VC decreased hepatic ALDH2 activity of mice fed HFD. Alda-1 attenuated oxidative stress, liver injury, and dysmetabolism in mice exposed to HFD+VC under these conditions. Importantly, alterations in mitochondrial function caused by VC and HFD were diminished by Alda-1. Previous studies have indicated that liver injury caused by HFD is mediated, at least in part, by enhanced mitochondrial autophagy (mitophagy). Here, Alda-1 suppressed PINK1/PARKIN-mediated mitophagy. Taken together, these results support the hypothesis that ALDH2 is a critical defense against mitochondrial injury caused by VC in experimental NAFLD. The ALDH2 activator Alda-1 conferred protection against liver damage under these conditions, most likely via increasing clearance of aldehydes and preserving mitochondrial respiratory function.Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

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