Targeting of CYP2E1 by miRNAs in Alcohol-Induced Intestine Injury

Authors

Hyejin Mun
Sungyul Lee
Suyoung Choi
Ji-Hoon Jeong
Seungbeom Ko
Yoo Lim Chun
Benjamin Deaton
Clay T Yeager
Audrey Boyette
Juliana Palmera
London Newman
Ping Zhou
Soona Shin
Dong-Chan Kim
Cari A Sagum
Mark T Bedford
Young-Kook Kim
Jaeyul Kwon
Junyang Jung
Jeong Ho Chang
Je-Hyun Yoon

Publication Date

7-1-2024

Journal

Molecular Cells

Abstract

Although binge alcohol-induced gut leakage has been studied extensively in the context of reactive oxygen species-mediated signaling, it was recently revealed that post-transcriptional regulation plays an essential role as well. Ethanol (EtOH)-inducible cytochrome P450-2E1 (CYP2E1), a key enzyme in EtOH metabolism, promotes alcohol-induced hepatic steatosis and inflammatory liver disease, at least in part by mediating changes in intestinal permeability. For instance, gut leakage and elevated intestinal permeability to endotoxins have been shown to be regulated by enhancing CYP2E1 mRNA and CYP2E1 protein levels. Although it is understood that EtOH promotes CYP2E1 induction and activation, the mechanisms that regulate CYP2E1 expression in the context of intestinal damage remain poorly defined. Specific miRNAs, including miR-132, miR-212, miR-378, and miR-552, have been shown to repress the expression of CYP2E1, suggesting that these miRNAs contribute to EtOH-induced intestinal injury. Here, we have shown that CYP2E1 expression is regulated post-transcriptionally through miRNA-mediated degradation, as follows: (1) the RNA-binding protein AU-binding factor 1 (AUF1) binds mature miRNAs, including CYP2E1-targeting miRNAs, and this binding modulates the degradation of corresponding target mRNAs upon EtOH treatment; (2) the serine/threonine kinase mammalian Ste20-like kinase 1 (MST1) mediates oxidative stress-induced phosphorylation of AUF1. Those findings suggest that reactive oxygen species-mediated signaling modulates AUF1/miRNA interaction through MST1-mediated phosphorylation. Thus, our study demonstrates the critical functions of AUF1 phosphorylation by MST1 in the decay of miRNAs targeting CYP2E1, the stabilization of CYP2E1 mRNA in the presence of EtOH, and the relationship of this pathway to subsequent intestinal injury.

Keywords

AU-binding factor 1, Cytochrome P450-2E1, Intestine, microRNA, Mammalian Ste20-like kinase 1

Comments

Supplementary Materials

PMID: 38901530