Early growth response-1 (Egr-1), an immediate early gene/zinc-finger transcription factor, is required for maximal stimulation of tumor necrosis factor α (TNF-α) transcription in response to lipopolysaccharide (LPS). Because chronic ethanol exposure sensitizes macrophages to LPS-stimulated TNF-α expression, we have investigated the role of Egr-1 in mediating increased LPS-stimulated TNF-α expression after chronic ethanol feeding. Furthermore, because TNF-α contributes to alcoholic liver injury, we tested the hypothesis that Egr-1 is required for the development of ethanol-induced fatty liver injury in wild type and egr-1 −/− mice.

Wild-type and egr-1 −/− mice were fed ethanol-containing diets or pair-fed control diets for 6 weeks.

Wild-type mice fed the ethanol diet developed hepatic steatosis characterized by micro- and macrovesicular lipid accumulation. However, egr-1 −/− mice did not develop steatosis after ethanol feeding. Alanine transferase and TNF-α concentrations in serum were increased after ethanol feeding in wild-type but not egr-1 −/− mice. In wild-type mice, challenge with LPS increased Egr-1 messenger RNA (mRNA) and DNA binding activity in liver; this response to LPS was enhanced after chronic ethanol feeding. LPS challenge also increased hepatic TNF-α mRNA and serum TNF-α to a greater extent after ethanol feeding compared with pair-fed wild-type mice. However, chronic ethanol feeding did not enhance LPS-stimulated TNF-α mRNA or serum TNF-α in egr-1 −/− mice.

These data show that Egr-1 contributes to increased LPS-mediated TNF-α expression after chronic ethanol and that the absence of Egr-1 prevents chronic ethanol-induced fatty liver, as well as increased sensitivity to LPS.