| ASH caused by chronic ethanol (EtOH) consumption, NASH associated with obesity/metabolic syndrome, and TASH in plastics factory workers have virtually identical histopathologies. Moreover, obesity and EtOH act synergistically to cause steatohepatitis. Such observations imply a similar or shared pathogenesis. In vivo, the liver responds to acute and chronic EtOH with a near doubling of EtOH metabolism and mitochondrial respiration beginning within 2-3 h after a single EtOH dose. Enhanced respiration allows more rapid oxidization NADH to NAD+ in support of NAD+-requiring metabolism of EtOH first to acetaldehyde (AcAld) and then to acetate by cytosolic EtOH dehydrogenase and mitochondrial aldehyde dehydrogenase-2 (ALDH2), respectively. Hepatic mitochondrial depolarization (mtDepo) accompanies increased respiration after EtOH, as visualized by intravital multiphoton microscopy. Simultaneously, voltage dependent anion channels (VDAC) close, the common route by which hydrophilic metabolites, but not neutral membrane-permeant aldehydes, move across the mitochondrial outer membrane. AcAld formation drives both mtDepo and VDAC closure after EtOH, and together mtDepo and VDAC closure promote selective detoxifying oxidation of AcAld by ALDH2. VDAC closure also inhibits mitochondrial β-oxidation to promote steatosis in hepatocytes with mtDepo. mtDepo then the stimulates mitophagy. These changes are reversible after acute EtOH, but chronically, as autophagic burden increases and processing becomes compromised, release of mitochondrial damage-associated molecular patterns (mtDAMPs) occurs that promotes inflammasome activation and fibrosis. Alda-1, an ALDH2 activator, accelerates AcAld elimination and decreases mtDepo, inflammation, and profibrotic changes after chronic EtOH. In NASH, oxidative stress and lipid peroxidation lead to formation of aldehydes like malondialdehyde (MDA) that are detoxified by ALDH2. MDA is 10-times more potent than AcAld at closing VDAC. Moreover, after Western diet (WD) feeding in mice, widespread hepatic mitochondrial depolarization (mtDepo) occurs at a very early stage, which is followed by increased mitophagy, impaired autophagic processing, and elevated serum mitochondrial DNA (mtDNA), a mtDAMP. Inflammation and fibrosis then follow. Vinyl chloride is used in plastics manufacturing. The liver metabolizes vinyl chloride to ClEtOH and then to ClAcAld, which then may produce TASH. Like AcAld and MDA, ClAcAld produces VDAC closure in a cellular assay. We propose that persistence of mtDepo and VDAC closure is a pathogenic tipping point that links adaptive mitochondrial aldehyde metabolism to maladaptive changes initiating onset and progression of ASH, NASH and TASH (NIAAA, NIDDK and NIEHS). |
