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The hypothesis that alcohol metabolism contributes to the pathogenesis of non-alcoholic fatty liver disease (NAFLD) dates back to 2000 when Cope et al 1 reported elevated alcohol concentration in the breath of ob/ob mice and demonstrated that breath alcohol concentration can be reduced by gut microbial intervention with neomycin. In the last 15 years, accumulating evidence in support of this hypothesis has been reported by several groups (reviewed at ref. 2), including the group led by Bergheim, who first reported elevated serum alcohol in NAFLD.3 Previous studies indicated that the elevated alcohol level in NAFLD is associated with increased representation of alcohol producing bacteria in the gut microbiome.4 ,5 However, a recent report by Bergheim and her colleagues suggested a very different mechanism for the alcohol spike in NAFLD.6 Their major findings include (1) alcohol level in the portal vein of ob/ob mice is comparable with that of lean mice although alcohol level in the vena cava of ob/ob mice is higher than that of lean animals and (2) alcohol dehydrogenase (ADH) activity and cytochrome P450 2E1 (CYP2E1) activity are lower in the liver of ob/ob mice than those of lean mice.
From these observations, it is reasonable to conclude that decreased ADH and CYP2E1 activities contribute to the elevated alcohol in the peripheral circulation. However, before firmly accepting this conclusion, we must consider one obvious caveat of this study. The intervention study presented in this paper was to treat the ob/ob mice with tumour necrosis factor-α antibody to boost the ADH activities.6 One would expect that elevated ADH activities would reduce serum alcohol levels. However, that did not occur. Further studies are needed in support of a causal relationship between decreased hepatic ADH activity and elevated serum alcohol level in ob/ob mice.
The decreased ADH and CYP2E1 activities in ob/ob mice contrast with increased alcohol metabolising genes, proteins and enzymatic activities in the livers of patients with NAFLD. Elevated CYP2E1 protein expression in the livers of NAFLD patients was first reported in 19987 and confirmed with an activity study by Chalasani et al.8 Our group observed that, at both mRNA and protein levels, all three major hepatic alcohol metabolising pathways (ADH, CYP2E1 and catalase) are highly elevated in paediatric NAFLD livers compared with healthy livers.9 Recently, we reported similar observations in adult NAFLD population.10
Another interesting observation by Bergheim and colleagues is that alcohol in the gut is not different between ob/ob mice and lean animals. This is a clear indication that the microbiome of ob/ob mice produces a similar amount of alcohol as the microbiome of lean animals. This observation contrasts with the report that the stools of patients with NAFLD exhibit higher levels of alcohol than that of the healthy subjects.4 In fact, two groups reported that the faecal microbiota in NAFLD has higher representations in alcohol producing microbes.4 ,5 For ethical reasons, data are not available for microbiota composition or alcohol concentration in the intestines of the patients with NAFLD.
In summary, data from several groups support the observation that the microbiome of patients with NAFLD produces more alcohol, which induced the expression of alcohol metabolising enzymes in liver. More importantly, alcohol metabolism promotes steatosis and oxidative stress in the liver, and therefore may represent a potent hit in NAFLD pathogenesis. The opposite phenomenon of decreased alcohol metabolising enzymes in the livers of ob/ob mice may explain why ob/ob mice do not spontaneously develop liver inflammation, and provides an excellent platform to investigate hepatic alcohol metabolism and its contribution to liver injury.
Funding This work was supported by the University at Buffalo Departmental Start-Up Fund (LZ) and the Tommy and Peter Fund, Inc., Buffalo, NY (SSB and LZ).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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