Identification of cytochrome CYP2E1 as critical mediator of alcohol effects on steatotic hepatocytes

Background & Aims: Several clinical studies proposed a strong causative link between the consumption of alcohol and progressive liver disease in obese individuals. However, it is incompletely understood how alcohol and obesity interact and whether the combined pathological effects are additive or synergistic. Here, we aimed to establish an in vitro model for joint effects of alcohol and steatosis in hepatocytes.

Methods and Results: Lipid accumulation in primary human hepatocytes was induced by incubation with the fatty acid oleate. Subsequently, steatotic and control hepatocytes were incubated with up to 50 mM alcohol.

In this dose range alcohol alone had only a minimal effect but significantly enhanced oleate induced lipogenesis and cellular triglyceride content, as well as lipid peroxidation, oxidative stress and NFkappaB-mediated pro-inflammatory gene expression. CYP2E1 inhibition or reactive oxygen species scavengers blunted these synergistic pathological effects of alcohol and steatosis. Moreover, under the experimental conditions used, alcohol induced autophagy in steatotic but not in control hepatocytes, and also this synergistic effect was mediated via CYP2E1. Further induction of autophagy ameliorated the joint effect of alcohol and oleate stimulation on cellular lipid accumulation and inflammatory gene expression while inhibition of autophagy further enhanced the dual pathological effects.

Conclusion: Our model indicates that alcohol and steatosis synergistically induce pathological as well as protective mechanisms in hepatocytes via CYP2E1. These findings may have important implications for the prognosis and treatment of alcoholic liver disease particularly in obese individuals.

Corresponding author: Mahli, Abdo

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