REDD1 upregulation via AP‐1 alleviates oxidative stress‐mediated liver injury

Abstract

Regulated in development and DNA damage responses 1 (REDD1) is an inducible gene in response to various stresses, which functions as a negative regulator of the mammalian target of rapamycin protein kinase in complex 1. In the present study, we identified the role of REDD1 under the oxidative stress‐mediated hepatocyte injury and its regulatory mechanism. REDD1 protein was increased in H2O2 or tert‐butylhydroperoxide (t‐BHP)‐treated hepatocytes· H2O2 also elevated REDD1 mRNA levels. This event was inhibited by antioxidants such as diphenyleneiodonium chloride, N‐acetyl‐L‐cysteine, or butylated hydroxy anisole. Interestingly, we found that H2O2‐mediated REDD1 induction was transcriptionally regulated by activator protein‐1 (AP‐1), and that overexpression of c‐Jun increased REDD1 protein levels and REDD1 promoter‐driven luciferase activity. Deletion of the putative AP‐1 binding site in proximal region of the human REDD1 promoter significantly abolished REDD1 transactivation by c‐Jun. A NF‐E2‐related factor 2 activator, tert‐butylhydroquinone treatment also elevated REDD1 levels, but it was independent on NF‐E2‐related factor 2 activation. Furthermore, we observed that REDD1 overexpression attenuated H2O2 or t‐BHP‐derived reactive oxygen species formation as well as cytotoxicity. Conversely, siRNA against REDD1 aggravated t‐BHP‐induced reactive oxygen species generation and cell death. In addition, we showed that REDD1 was induced by in vitro or in vivo ischemia/reperfusion model. Our results demonstrate that REDD1 induction by oxidative stress is mainly transcriptionally regulated by AP‐1, and protects oxidative stress‐mediated hepatocyte injury. These findings suggest REDD1 as a novel molecule that reduced susceptibility to oxidant‐induced liver injury.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.