Early growth response-1 transcription factor is essential for ethanol-induced fatty liver injury in mice.
OBJECTIVE
Early growth response-1 (Egr-1), an immediate early gene/zinc-finger transcription factor, is required for maximal stimulation of tumor necrosis factor alpha (TNF-alpha) transcription in response to lipopolysaccharide (LPS). Because chronic ethanol exposure sensitizes macrophages to LPS-stimulated TNF-alpha expression, we have investigated the role of Egr-1 in mediating increased LPS-stimulated TNF-alpha expression after chronic ethanol feeding. Furthermore, because TNF-alpha 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.


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


RESULTS
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-alpha 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-alpha mRNA and serum TNF-alpha to a greater extent after ethanol feeding compared with pair-fed wild-type mice. However, chronic ethanol feeding did not enhance LPS-stimulated TNF-alpha mRNA or serum TNF-alpha in egr-1 -/- mice.


CONCLUSIONS
These data show that Egr-1 contributes to increased LPS-mediated TNF-alpha expression after chronic ethanol and that the absence of Egr-1 prevents chronic ethanol-induced fatty liver, as well as increased sensitivity to LPS.
McMullen
Megan R
MR
Department of Nutrition, Case Western Reserve University, Cleveland, Ohio 44106-4906, USA.
Pritchard
Michele T
MT
Wang
Qifang
Q
Millward
Carrie A
CA
Croniger
Colleen M
CM
Nagy
Laura E
LE
D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology / Q000633:toxicity*; D004268:DNA-Binding Proteins / Q000502:physiology*; D004032:Diet; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1; D000431:Ethanol / Q000494:pharmacology / Q000633:toxicity*; D005235:Fatty Liver, Alcoholic / Q000503:physiopathology*; D005260:Female; D017874:Immediate-Early Proteins / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000502:physiology; D016335:Zinc Fingers
D002492:Central Nervous System Depressants; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; D008070:Lipopolysaccharides; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol