Z Gastroenterol 2015; 53 - A3_17
DOI: 10.1055/s-0035-1568037

Identification of cytochrome CYP2E1 as critical mediator of synergistic effects of alcohol and cellular lipid accumulation in hepatocytes in vitro

A Mahli 1, WE Thasler 2, E Patsenker 3, S Müller 4, F Stickel 3, M Müller 1, HK Seitz 4, AI Cederbaum 5, C Hellerbrand 1
  • 1University Hospital Regensburg, Department of Internal Medicine I, Regensburg, Germany
  • 2Grosshadern Tissue Bank and Center for Liver Cell Research, Department of Surgery, Munich, Germany
  • 3University of Bern, Murtenstrasse 35, CH-3010, Department of Clinical Research, Bern, Switzerland
  • 4Centre for Alcohol Research, University of Heidelberg, Department of Medicine (Gastroenterogy), Salem Medical Centre, 69121 Heidelberg, Germany
  • 5Icahn School of Medicine at Mount Sinai, Department of Pharmacology and Systems Therapeutics, New York, NY 10029, USA

Clinical studies propose a causative link between the consumption of alcohol and the development and progression of liver disease in obese individuals. However, it is incompletely understood how alcohol and obesity interact and whether the combined effects are additive or synergistic.

The aim of this study was to establish an in vitro model for joint effects of alcohol and steatosis in hepatocytes in vitro.

Methods and Results: Lipid accumulation in primary human hepatocytes (PHH) was induced by incubation with fatty acids. Subsequently, steatotic and control hepatocytes were incubated with up to 50 mM alcohol. This alcohol concentration on its own revealed only minimal effects but significantly enhanced fatty acid induced lipogenesis and cellular triglyceride content compared to control cells. Similarly, lipid peroxidation, oxidative stress and pro-inflammatory gene expression, as well as CYP2E1 levels and activity were synergistically induced by alcohol and steatosis. CYP2E1 inhibition blunted these synergistic pathological effects. Notably, alcohol and cellular steatosis also induced autophagy in a synergistic manner, and also this was mediated via CYP2E1. Further induction of autophagy ameliorated the joint effects of alcohol and free fatty acids on hepatocellular lipid accumulation and inflammatory gene expression while inhibition of autophagy further enhanced the dual pathological effects. Further analysis revealed that combined stimulation with alcohol and free fatty acids induced JNK-activation and JUN-phosphorylation significantly more than either of the two stimuli alone. Conversely, JNK inhibition abrogated the induction of autophagy in steatotic hepatocytes by alcohol.

Conclusion: In summary, our data indicate that alcohol induces not only pathological but also protective mechanisms in steatotic hepatocytes via CYP2E1 mediated JNK induction. These findings may have important implications on the prognosis and treatment of alcoholic liver disease particularly in obese individuals.

Corresponding author: Hellerbrand, Claus

E-Mail: claus.hellerbrand@ukr.de