title: Is nonalcoholic fatty liver disease an endogenous alcoholic fatty liver disease? - A mechanistic hypothesis.
abstract: Nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) are so similar that only a detailed history of alcohol intake can distinguish one from the other. Because subjects with NAFLD produce significantly more endogenous ethanol (EE) than controls, some researchers suspected that these similarities are not merely coincidental. For this reason, it was attempted to show that NAFLD is actually an endogenous alcoholic fatty liver disease (EAFLD). However, negligible blood-alcohol concentration (BAC) and the inability of gut microbiota to produce hepatotoxic concentrations of EE rejected this hypothesis. To clarify these conflicting results, we provide a mechanistic framework explaining how NAFLD may be an EAFLD. First of all, the key finding is that ethanol is a prodrug, enabling the idea that AFLD may develop with negligible/absent BAC. Second, extrahepatic acetaldehyde (ACD) alone recapitulates AFLD and is about 330-fold more hepatotoxic than that generated inside the liver. Third, gut microbiota can even produce much larger amounts of EE than those currently considered cirrhotogenic for man. Fourth, an extensive gut-liver axis first-pass metabolism of ethanol prevents the development of significant BAC in NAFLD. Fifth, all genes involved in EE metabolism are upregulated in the livers of patients with nonalcoholic steatohepatitis (NASH). Last, overexpression of the gene encoding alcohol dehydrogenase (ADH) 4 implicates liver exposure to high concentrations of EE. In conclusion, this work provides mechanistic explanation supporting the assumption that NAFLD may indeed be an EAFLD. If validated by further testing, the hypothesis may help develop novel therapeutic and preventive strategies against this ubiquitous condition.
authors.affiliation: Universidade Federal do Rio Grande do Norte, Departamento de Medicina Clínica, Divisão de Gastroenterologia, Av. Nilo Peçanha, 620 - CEP 59012-300 Natal/RN, Brazil. Electronic address: coutimed@supercabo.com.br.
authors.forename: Ivanildo Coutinho
authors.initials: IC
authors.lastname: de Medeiros
authors.affiliation: Universidade Federal do Rio Grande do Norte, Departamento de Medicina Clínica, Divisão de Endocrinologia, Av. Nilo Peçanha, 620 - CEP 59012-300 Natal/RN, Brazil.
authors.forename: Josivan Gomes
authors.initials: JG
authors.lastname: de Lima
mesh_terms: D000079:Acetaldehyde / Q000378:metabolism*; D000431:Ethanol / Q000378:metabolism*; D005235:Fatty Liver, Alcoholic / Q000378:metabolism* / Q000382:microbiology; D000069196:Gastrointestinal Microbiome / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism* / Q000382:microbiology
chemical_list: D000431:Ethanol; D000079:Acetaldehyde