Endogenous Alcohol in NAFLD

Non-alcoholic fatty liver disease (NAFLD) is by now one of the most common liver diseases worldwide. Results of human and animal studies suggest that genetic predisposition and lifestyle like decreased physical activity, general overnutrition but also a diet rich in fat and/or sugar are risk factors in the development of this liver disease. However, in spite of intense research efforts throughout the last decades, molecular mechanisms involved have not yet been fully understood and universally accepted prevention and therapeutic strategies are still lacking. In recent years it has been shown that alterations in the gut like changes in intestinal bacterial composition and of gut barrier function may also be critical in the onset but also in more progressive stages of the disease like steatohepatitis. Furthermore, it has been shown that patients with NAFLD frequently have elevated fasting blood alcohol levels, even in the absence of ethanol consumption. Indeed it has been proposed that the so called endogenous ethanol synthesis may be involved in the intestinal barrier dysfunction found in patients with NAFLD. Results of our own group suggest that the enzyme-dependent metabolism of ethanol in the liver is disturbed in settings of NAFLD. However, findings are still contradictory and molecular mechanisms involved have not yet been fully understood. Accordingly, the proposed project aims to further delineate if alterations of intestinal microbiota e.g. towards a more ethanol building bacterial population or other mechanisms like an altered metabolism of ethanol in the liver are involved in the elevated fasting alcohol levels found in patients with NAFLD. Furthermore, implications of these alterations for the development of NAFLD will be assessed.

Non-alcoholic fatty liver disease (NAFLD), now referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), is by now the most common liver disease worldwide affecting approximately 30% of the population. Results of epidemiological and experimental studies suggest that not only a general overnutrition, a `Western dietary pattern and a (genetic) predisposition may be critical in the development of MASLD, but also alterations of intestinal microbiota and barrier function may be important for the development and progression of the disease. Moreover, studies suggest that even in the absence of any alcohol intake, patients with MASLD often have elevated fasting blood ethanol levels. It has been suggested that the latter may be attributed to an increased ethanol synthesis by intestinal bacteria. Results of our own group suggest that alterations in the metabolization of ethanol through alcohol dehydrogenase (ADH) in liver tissue may be critical, too. However, mechanisms underlying the elevation of fasting ethanol levels in patients with MASLD are not yet fully understood. Starting from this background, the main aim of the project was to further determine the role of ADH-dependent ethanol metabolism in the liver in the elevation of fasting ethanol levels in patients with MASLD and to determine mechanism involved. Results of the project suggest that the elevation of fasting ethanol levels in patients with MASLD is related to an impaired activity of ADH and disease severity in humans. Moreover, results of in-vitro and in-vivo studies suggest that the alterations in ADH activity seem to depend on the induction of a specific cytokine, tumor necrosis factor alpha (TNF).