- Hellerbrand, University Hospital, Dept. of Internal Medicine, Regensburg
Clinical studies propose a causative link between obesity and the development and progression of alcoholic liver disease (ALD). However, it is only incompletely understood how alcohol and obesity interact and whether the combined effects are additive or synergistic. We have developed in vitro and in vivo models to study isolated as well as combined effects of alcohol and steatosis. Incubation of primary human hepatocytes with free fatty acids or feeding high fat Western type diets to mice were used to induce hepatocellular steatosis. Application of alcohol induced significantly higher oxidative stress and proinflammatory gene expression in steatotic hepatocytes or livers, respectively. Noteworthy, this was observed with alcohol concentrations that did show only minimal effects on steatosis and inflammation on its own. In combination with steatosis, alcohol markedly induced CYP2E1 expression levels and activity, and CYP2E1 inhibition abrogated the synergistic effects of alcohol and steatosis on oxidative stress and inflammation. However, we also observed that the alcohol-steatosis connection triggers hepatoprotective mechanisms such as autophagy. One may speculate whether individual factors tipping the balance on the one or the other side of detrimental or beneficial joint effects of alcohol and steatosis account at least in part for the high variation in the clinical course of alcoholic liver disease.