Vinyl chloride-induced interaction of nonalcoholic and toxicant-associated steatohepatitis: Protection by the ALDH2 activator Alda-1

Redox Biol. 2019 Jun;24:101205. doi: 10.1016/j.redox.2019.101205. Epub 2019 Apr 19.

Abstract

Vinyl 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.

Keywords: Aldehyde dehydrogenase; Angiosarcoma; Nonalcoholic fatty liver disease; PVC; Toxicant-associated steatohepatitis; Vinyl chloride.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aldehyde Dehydrogenase, Mitochondrial / metabolism
  • Animals
  • Autophagy / drug effects
  • Benzamides / pharmacology
  • Benzodioxoles / pharmacology
  • Enzyme Activation / drug effects
  • Fatty Liver / chemically induced*
  • Fatty Liver / metabolism*
  • Fatty Liver / pathology
  • Fatty Liver / prevention & control
  • Male
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Neutrophil Infiltration
  • Neutrophils / immunology
  • Neutrophils / metabolism
  • Neutrophils / pathology
  • Non-alcoholic Fatty Liver Disease / etiology*
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Non-alcoholic Fatty Liver Disease / pathology
  • Non-alcoholic Fatty Liver Disease / prevention & control
  • Oxidative Stress / drug effects
  • Phenotype
  • Protective Agents / pharmacology
  • Vinyl Chloride / adverse effects*

Substances

  • Benzamides
  • Benzodioxoles
  • N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide
  • Protective Agents
  • ALDH2 protein, mouse
  • Aldehyde Dehydrogenase, Mitochondrial
  • Vinyl Chloride