MEK1/2 inhibitors induce class I alcohol dehydrogenase (ADH1) expression by regulating farnesoid X receptor in hepatic cell lines and C57BL/6J mouse
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Published on: May 25, 2017
Xiaolin Wang1, Yanfang Yang1, Yuanli Chen2
1College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China.
Background:
Alcohol is mainly catabolized by class I alcohol dehydrogenase (ADH1) in liver. ADH deficiency can aggravate ethanol-induced tissue injury. Extracellular signal-regulated kinases 1/2 (ERK1/2) is involved in alcohol metabolism. However, the relationship between ERK1/2 and ADH1 remains unclear.
Methods And Results:
To inhibit ERK1/2, HepG2 and BNL cells were treated with mitogen-activated protein kinases 1/2 (MEK1/2) inhibitors (U0126 and PD98059), and C57BL/6J mice were fed U0126. After treatment, the protein and mRNA expression of ADH1 were determined by Western blot and quantitative real time-PCR. The activity of ADH1 promoter was detected using luciferase assay. The results showed MEK1/2 inhibitors significantly increased ADH1 protein expression by inducing its transcription activity. Then we demonstrated a farnesoid X receptor (FXR) response element (FXRE) in ADH1 promoter by ChIP assay. To test whether FXR mediates the induction of MEK1/2 inhibitors on ADH1, HepG2 cells were transfected with FXR siRNA or ADH1 promoters with FXRE mutation. We found both FXR siRNA and FXRE mutation in ADH1 promoter abolished MEK1/2 inhibitors-induced ADH1 expression, indicating the activation of MEK1/2 inhibitors on ADH1 depends on FXR.
Conclusions:
Our findings revealed inhibition of ERK1/2 can significantly increase ADH1 expression, indicating MEK1/2 inhibitors may possess potential application in alcohol-related diseases.
