SIRT1 attenuates palmitate-induced endoplasmic reticulum stress and insulin resistance in HepG2 cells via induction of oxygen-regulated protein 150

Jung, Tae Woo; Lee, Kyoungtae; Lee, Myung Won; Ka, Kang-Hyeon

doi:10.1016/j.bbrc.2012.04.129

Cited by 75 publications

(53 citation statements)

References 16 publications

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“…Consistent with the results of cell culture study, animal studies showed that SRT1720 reduced the tubular expression of ER stress protein (GRP78). In agreement with our study, it has been reported that SIRT1 is able to attenuate palmitate-induced ER stress in HepG2 cells [33] and also obesity-induced ER stress in the liver [34]. Similarly, it has been reported that inhibitory effects of exendin-4 on the palmitate-induced ER stress is mediated through activation of SIRT1 [35].…”

Section: Discussionsupporting

confidence: 79%

Up-Regulation of SIRT1 Reduces Endoplasmic Reticulum Stress and Renal Fibrosis

Chang

Kim

Baek

et al. 2016

Nephron

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Background: Endoplasmic reticulum (ER) stress is emerging as an important factor in the development of organ fibrosis. Therefore, modulation of ER stress may serve as one of the possible therapeutic approaches to renal fibrosis. SIRT1, a class III histone deacetylase, has been found to exert beneficial effects in kidney diseases. However, it is largely unknown whether and how SIRT1 suppresses the ER stress. We postulated that upregulation of SIRT1 would suppress the ER stress through induction of heme oxygenase-1 (HO-1) and thioredoxin. Methods: HK-2 tubular cells, experimental mouse models of tunicamycin (TM)-induced ER stress and unilateral ureteral obstruction (UUO) were used. Expression of ER stress-induced protein was measured by Western blot analysis and immunohistochemical staining. ER stress was induced by chemical ER stress inducers [TM [,]thapsigargin (TG)] and non-chemical inducers such as angiotensin II, aldosterone, high glucose and albumin. Results: SIRT1 activator (SRT1720) induced SIRT1 expression in a time- and dose-dependent manner in HK-2 cells. SRT1720 suppressed the TM- or TG-induced ER stress, as shown by inhibition of TM- or TG-induced upregulation of glucose-related protein 78 (GRP78), phosphor-specific eukaryotic translation initiation factor-2α and C/EBP homologous protein through HO-1 and thioredoxin, which were abolished by pretreatment with SIRT1 inhibitor (sirtinol). SRT1720 also suppressed the ER stress induced by angiotensin II, aldosterone, high glucose and albumin. In animal studies, treatment with SRT1720 reduced the tubular expression of GRP78 and increased the expression of HO-1 and thioredoxin. SRT1720 also reduced the UUO-induced renal fibrosis. Conclusion: SIRT1 may serve as a promising therapeutic target by reducing ER stress and fibrosis.

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Section: Discussionsupporting

confidence: 79%

Up-Regulation of SIRT1 Reduces Endoplasmic Reticulum Stress and Renal Fibrosis

Chang

Kim

Baek

et al. 2016

Nephron

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“…Ghosh et al (12) have demonstrated that SIRT1 associates with eIF2-␣ and negatively regulates cellular stress responses. Moreover, it was also reported that SIRT1 attenuates ER stress in vitro and in vivo (18,30). Therefore, the role of SIRT1 as a negative regulator for ER stress response is conserved from C. elegans to mammals, indicating a crucial link between SIRT1 and ER stress.…”

Section: Discussionmentioning

confidence: 99%

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

Koga

Suico

Shimasaki

et al. 2015

Journal of Biological Chemistry

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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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“…In cardiovascular disease, it is protective against ischaemia/reperfusion injury, but stimulates cardiac hypertrophy [27]. In T2DM, SIRT1 is protective against insulin resistance and endoplasmic reticulum stress [28]. It mediates many of its protective effects via deacetylation of its target proteins, which include p53, FOXO (forkhead box O) transcription factors and PGC-1α (peroxisome-proliferator-activated receptor γ co-activator-1α) [29].…”

Section: Introductionmentioning

confidence: 99%

Epigenetic regulation of angiotensin-converting enzyme 2 (ACE2) by SIRT1 under conditions of cell energy stress

et al. 2013

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ACE2 (angiotensin-converting enzyme 2) counterbalances the actions of ACE (angiotensin-converting enzyme) by metabolizing its catalytic product, the vasoactive and fibrogenic peptide AngII (angiotensin II), into Ang-(1-7) [angiotensin-(1-7)]. Enhanced ACE2 expression may be protective in diabetes, cardiovascular disease and cancer. However, relatively little is known about the specific physiological factors regulating ACE2 expression. In the present paper, we show, by Western blotting and qPCR (quantitative real-time PCR), that ACE2 expression is increased under conditions of cell stress, including hypoxic conditions, IL (interleukin)-1β treatment and treatment with the AMP mimic AICAR (5-amino-4-imidazolecarboxamide riboside). The NAD+-dependent deacetylase SIRT1 (silent information regulator T1) was found to be up-regulated after AICAR treatment but, conversely, was down-regulated after IL-1β treatment. ChIP analysis demonstrated that SIRT1 bound to the ACE2 promoter and that binding was increased after AICAR treatment, but decreased after IL-1β treatment. Inhibition of SIRT1 activity ablated the AICAR-induced increase in ACE2. In conclusion, we have established that the expression of the ACE2 transcript is controlled by the activity of SIRT1 under conditions of energy stress.

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SIRT1 attenuates palmitate-induced endoplasmic reticulum stress and insulin resistance in HepG2 cells via induction of oxygen-regulated protein 150

Cited by 75 publications

References 16 publications

Up-Regulation of SIRT1 Reduces Endoplasmic Reticulum Stress and Renal Fibrosis

Up-Regulation of SIRT1 Reduces Endoplasmic Reticulum Stress and Renal Fibrosis

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

Epigenetic regulation of angiotensin-converting enzyme 2 (ACE2) by SIRT1 under conditions of cell energy stress

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