Why only a subpopulation (about 15%) of humans develops
liver cirrhosis due to alcohol is a critical as yet unanswered question. Liver-specific depletion of augmenter of liver regeneration (ALR)
protein in mice causes robust steatosis and hepatocyte apoptosis by 2 weeks; these pathologies regress subsequently with return of ALR expression even at lower than control levels, but the mice develop modest
steatohepatitis by 8 weeks. We aimed to investigate whether chronic alcohol ingestion promotes excessive hepatic
fibrosis in these ALR-deficient mice. Liver-specific ALR-deficient and wild type (WT) female mice (8-10 weeks old) were placed on 4% alcohol-supplemented or isocaloric diet for 4 weeks. Liver sections were examined for histopathology, and parameters of steatosis and
fibrosis were quantified. The
mRNA expression of alcohol dehydrogenase-1,
acetaldehyde dehydrogenase-1 and
cytochrome P450-2E1 increased in WT mice but decreased in ALR-deficient mice upon alcohol ingestion. While alcohol induced steatosis and mild
inflammation in WT mice, ALR-deficient mice showed minimal steatosis, strong hepatocellular injury and
inflammation, prominent ductular proliferation, and robust
fibrosis. Compared to the WT mice, alcohol feeding of ALR-deficient mice resulted in significantly greater increase in hepatic TNFα and TGFβ, and oxidative stress; there was also hepatic
iron accumulation, robust lipid peroxidation and
mitochondrial DNA damage. Importantly, similar to ALR-deficient mice, lower hepatic ALR levels in human
alcoholic liver cirrhosis were associated with increased
iron content, reduced expression of
alcohol dehydrogenase and
acetaldehyde dehydrogenase, and elevated fibrogenic markers. We conclude that ALR deficiency or anomaly can play a critical role in alcohol-induced hepatic
fibrosis/
cirrhosis, mechanisms of which may involve dysregulation of alcohol metabolism and
iron homeostasis, mitochondrial damage and oxidative injury.