Acute ethanol preexposure promotes liver regeneration after partial hepatectomy in mice by activating ALDH2

Abstract

It is known that chronic ethanol significantly impairs liver regeneration. However, the effect of acute ethanol exposure on liver regeneration remains largely unknown. To address this question, C57Bl6/J mice were exposed to acute ethanol (6 g/kg intragastrically) for 3 days, and partial hepatectomy (PHx) was performed 24 h after the last dose. Surprisingly, acute ethanol preexposure promoted liver regeneration. This effect of ethanol did not correlate with changes in expression of cell cycle regulatory genes (e.g., cyclin D1, p21, and p27) but did correlate with protection against the effect of PHx on indices of impaired lipid and carbohydrate metabolism. Ethanol preexposure protected against inhibition of the oxidant-sensitive mitochondrial enzyme, aconitase. The activity of aldehyde dehydrogenase 2 (ALDH2) was significantly increased by ethanol preexposure. The effect of ethanol was blocked by inhibiting (Daidzin) and was mimicked by activating (Alda-1) ALDH2. Lipid peroxides are also substrates for ALDH2; indeed, alcohol preexposure blunted the increase in lipid peroxidation (4OH-nonenal adducts) caused by PHx. Taken together, these data suggest that acute preoperative ethanol exposure "preconditions" the liver to respond more rapidly to regenerate after PHx by activating mitochondrial ALDH2, which prevents oxidative stress in this compartment. aldehyde dehydrogenase 2; alcohol; liver regeneration; oxidative stress THE LIVER HAS TREMENDOUS REGENERATIVE capacity that distinguishes it from other vital organs (e.g., the brain, heart, and lungs) that are far less able to replace functional tissue. As the main detoxifying organ in the body, the liver is prone to toxic injury. Due to its regenerative properties, however, the liver is able to restore to full size and ensure survival. In experimental models (e.g., mice), full regeneration occurs within 7-10 days (36). Although hepatocytes rarely proliferate in the healthy adult liver, virtually all surviving hepatocytes replicate at least once after 70% partial hepatectomy (PHx).In addition to hepatocyte proliferation, there is a tightly coordinated response to complement the regenerative process (34). Perturbations of this complex and synchronized response can impact normal tissue recovery from injury or damage. Indeed, it is now clear that impaired regeneration and/or restitution is critical to the chronicity of numerous hepatic diseases. Studies have shown that chronic ethanol (EtOH) exposure delays the induction of hepatocyte DNA synthesis in response to PHx (20). This effect of chronic ethanol may contribute to impaired regeneration and restitution from damage associated with alcoholic liver disease.In contrast to chronic exposure, little is known about the effect of acute ethanol administration on liver regeneration. Under some conditions, acute and chronic ethanol exposure mediate similar responses in the organ. For example, both acute and chronic ethanol exposure enhance lipopolysaccharide-induced liver damage (1, 6). Should acute ethanol exposure also impair...

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