Downregulation of mitogen-activated protein kinases (MAPKs) in chronic ethanol-induced fatty liver

Abstract

Mitogen-activated protein kinases (MAPKs) are versatile proteins that have been suggested to be involved in the regulation of lipid metabolism. This study was designed to investigate the responses of MAPK signaling to chronic ethanol exposure in vivo and in vitro, and try to explore its role in the pathogenesis of alcoholic fatty liver (AFL). Mice were fed with Lieber-Decarli liquid diet (5% ethanol, w/v) for 4 weeks to induce fatty liver, and the chronological changes of MAPK phosphorylation were measured using western blotting. We found that chronic ethanol feeding led to accumulation of triglyceride (TG), decreased phosphorylation of MAPKs, decreased protein level of peroxisomal proliferator activation receptor α (PPARα), and increased protein expression of cytochrome P4502E1 (CYP2E1) in mice liver. In vitro study showed that overexpression of CYP2E1 blunted the response of MAPKs to ethanol, and MAPK phosphatase 1 (MKP-1) knockdown by siRNA led to upregulation of PPARα protein level. Lastly, epidermal growth factor (EGF), a well-known MAPK activator, significantly suppressed chronic ethanol-induced hepatic fat accumulation and decline of PPARα expression in mice liver. Collectively, MAPK suppression, possibly due to the activation of hepatic CYP2E1, may be involved in chronic ethanol-induced hepatic steatosis.

Keywords:

• Alcoholic fatty liver
• mitogen-activated protein kinases
• cytochrome P4502E1
• peroxisomal proliferator activation receptor α
• epidermal growth factor

Disclosure statement

The authors declare that there are no conflicts of interest.

Additional information

Funding

This work was supported by the National Science Foundation of China [Grant No. 81473004], the Key Research and Development Project of Shandong Province [Grant No. 2017GSF18122], and the Young Scholars Program of Shandong University [Grant No. 2015WLJH52].