Aldehyde dehydrogenase 2 deficiency ameliorates alcoholic fatty liver but worsens liver inflammation and fibrosis in mice

Abstract

Aldehyde dehydrogenase 2 (ALDH2) is the major enzyme that metabolizes acetaldehyde produced from alcohol metabolism. Approximately 40~50% of East Asians carry an inactive ALDH2 gene and exhibit acetaldehyde accumulation after alcohol consumption. However, the role of ALDH2 deficiency in the pathogenesis of alcoholic liver injury remains obscure. In the present study, wild-type and ALDH2−/− mice were subjected to ethanol feeding and/or carbon tetrachloride (CCl4) treatment, and liver injury was assessed. Compared with wild-type mice, ethanol-fed ALDH2−/− mice had higher levels of malondialdehyde-acetaldehyde (MAA) adduct and greater hepatic inflammation, with higher hepatic IL-6 expression but surprisingly lower levels of steatosis and serum ALT. Higher IL-6 levels were also detected in ethanol-treated precision-cut-liver-slices from ALDH2−/− mice and in Kupffer cells isolated from ethanol-fed ALDH2−/− mice than those levels in wild-type mice. In vitro incubation with MAA enhanced the LPS-mediated stimulation of IL-6 production in Kupffer cells. In agreement with these findings, hepatic activation of the major IL-6 downstream signaling molecule signal transducer and activator of transcription 3 (STAT3) was higher in ethanol-fed ALDH2−/− mice than in wild-type mice. An additional deletion of hepatic STAT3 increased steatosis and hepatocellular damage in ALDH2−/− mice. Finally, ethanol-fed ALDH2−/− mice were more prone to CCl4-induced liver inflammation and fibrosis than ethanol-fed wild-type mice. Conclusions: ALDH2−/− mice are resistant to ethanol-induced steatosis but prone to inflammation and fibrosis via MAA-mediated paracrine activation of IL-6 in Kupffer cells. These findings suggest that alcohol, via acetaldehyde and its associated adducts, stimulates hepatic inflammation and fibrosis independent from causing hepatocyte death, and that ALDH2-deficient individuals may be resistant to steatosis and blood ALT elevation, but are prone to liver inflammation and fibrosis following alcohol consumption.

The Kampo formula “Juzen-taiho-to” exerts protective effects on ethanol-induced liver injury in mice

“…Kwon et al reported increased levels of inflammatory cytokines in aldh2 knockout mice (Kwon et al, 2014). Our results show that pretreatment with JTX did not induce a significant decrease in the levels of Cyp2e1 and aldh2.…”

Roles of defective ALDH2 polymorphism on liver protection and cancer development

“…In a subsequent study, the decrease of ALT level in Aldh2 knockout mice was reported to be sustained for as long as the ethanol loading was administered, whereas wild type mice showed elevation of serum ALT [60]. Moreover, a liver injury model induced with a high-fat diet and carbon tetrachloride also showed lower serum ALT values in Aldh2 knockout mice than in wild type mice [61].…”

“…A different mechanism was suggested using liver injury models, in which interleukin-6-induced signal transducer and activator of transcription 3 relieve hepatic steatosis and result in lower serum ALT levels [61]. Supporting this finding, Yokoyama and colleagues [69] performed an epidemiological study on Japanese alcoholic men and reported that the serum triglyceride concentration was lower in ALDH2*1/*2 carriers than in ALDH2*1/*1 carriers (the least squares means adjusted for age and drinking amount were 103 and 113 mg/dL, respectively).…”

“…For example, the liver injury model mentioned above suggested protective effects such as inhibition of fatty degeneration; nevertheless, adverse effects were also reported, such as aggravation of the inflammatory response and fibrosis [61]. Simple ethanol administration does not cause such a marked discrepancy; however, hepatocyte ballooning was observed only in Aldh2 knockout mice in spite of their lower TNFa and serum ALT levels [59].…”

Genetic Basis of Alcoholic and Nonalcoholic Fatty Liver Disease

“…Around 50 % of East Asian subjects carry an inactive ALDH2 gene and exhibit acetaldehyde accumulation after alcohol consumption. Interestingly, compared with wild-type mice, ethanol-fed ALDH2-/-mice had higher levels of malondialdehyde-acetaldehyde (MAA) adduct and greater hepatic infl ammation, with higher hepatic interleukin (IL)-6 expression but lower levels of steatosis and serum alanine aminotransferase (ALT) [ 62 ].…”