Endoplasmic Reticulum (ER) Stress Induces Sirtuin 1 (SIRT1) Expression via the PI3K-Akt-GSK3β Signaling Pathway and Promotes Hepatocellular Injury

Abstract

Sirtuin 1 (SIRT1), an NAD؉ -dependent histone deacetylase, plays crucial roles in various biological processes including longevity, stress response, and cell survival. Endoplasmic reticulum (ER) stress is caused by dysfunction of ER homeostasis and exacerbates various diseases including diabetes, fatty liver, and chronic obstructive pulmonary disease. Although several reports have shown that SIRT1 negatively regulates ER stress and ER stress-induced responses in vitro and in vivo, the effect of ER stress on SIRT1 is less explored. In this study, we showed that ER stress induced SIRT1 expression in vitro and in vivo. We further determined the molecular mechanisms of how ER stress induces SIRT1 expression. Surprisingly, the conventional ER stress-activated transcription factors XBP1, ATF4, and ATF6 seem to be dispensable for SIRT1 induction. Based on inhibitor screening experiments with SIRT1 promoter, we found that the PI3K-Akt-GSK3␤ signaling pathway is required for SIRT1 induction by ER stress. Moreover, we showed that pharmacological inhibition of SIRT1 by EX527 inhibited the ER stress-induced cellular death in vitro and severe hepatocellular injury in vivo, indicating a detrimental role of SIRT1 in ER stress-induced damage responses. Collectively, these data suggest that SIRT1 expression is up-regulated by ER stress and contributes to ER stress-induced cellular damage.The endoplasmic reticulum (ER) 2 is an important organelle functioning in protein folding, transport, processing, and storage of calcium ion. Homeostasis of ER is crucial for cellular activity and survival (1-3). Intracellular and extracellular conditions that interfere with ER function lead to the accumulation of unfolded proteins in the ER, resulting in ER stress. Cells exposed to ER stress activate the unfolded protein response (UPR), which consists of three major branches: the activating transcription factor (ATF) 6, inositol-requiring enzyme (IRE) 1-X-box binding protein (XBP) 1, and PERK-eIF2␣-ATF4 pathways (4). These signaling pathways include both translational and transcriptional control mechanisms that reduce protein synthesis, increase the protein folding capacity by up-regulating the transcription of molecular chaperones, and activate the ER-associated protein degradation. By using these systems, living organisms maintain homeostasis against various stress conditions (4). Thus, malfunction of ER stress responses is associated with various diseases including diabetes, fatty liver, neurodegeneration, and chronic obstructive pulmonary disease (5-7).Sirtuins are the mammalian orthologues of the yeast Sir2 protein that is involved in chromatin silencing and lifespan regulation. The mammalian Sirtuin 1 (SIRT1) gene encodes a nicotinamide adenosine dinucleotide (NAD ϩ )-dependent histone deacetylase that is the closest structural ortholog of the yeast Sir2 protein (8,9). Although the yeast Sir2 protein has been extensively characterized as a histone deacetylase, the mammalian SIRT1 protein deacetylates not only histone but also nonhistone s...

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