Next Article in Journal
Transcriptome-Wide Identification and Expression Profiling Analysis of Chrysanthemum Trihelix Transcription Factors
Next Article in Special Issue
Endoplasmic Reticulum Stress and Associated ROS
Previous Article in Journal / Special Issue
The Role of Endoplasmic Reticulum Stress and Unfolded Protein Response in Atherosclerosis
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 17
Issue 2
10.3390/ijms17020192
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Pharmacological Modulators of Endoplasmic Reticulum Stress in Metabolic Diseases

by
Tae Woo Jung
and
Kyung Mook Choi
*
Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul 152-703, Korea
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2016, 17(2), 192; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17020192
Submission received: 26 December 2015 / Revised: 20 January 2016 / Accepted: 27 January 2016 / Published: 1 February 2016
(This article belongs to the Special Issue Modulators of Endoplasmic Reticulum Stress)
Browse Figure
Versions Notes

Abstract

:
The endoplasmic reticulum (ER) is the principal organelle responsible for correct protein folding, a step in protein synthesis that is critical for the functional conformation of proteins. ER stress is a primary feature of secretory cells and is involved in the pathogenesis of numerous human diseases, such as certain neurodegenerative and cardiometabolic disorders. The unfolded protein response (UPR) is a defense mechanism to attenuate ER stress and maintain the homeostasis of the organism. Two major degradation systems, including the proteasome and autophagy, are involved in this defense system. If ER stress overwhelms the capacity of the cell’s defense mechanisms, apoptotic death may result. This review is focused on the various pharmacological modulators that can protect cells from damage induced by ER stress. The possible mechanisms for cytoprotection are also discussed.

Graphical Abstract

1. Introduction

The endoplasmic reticulum (ER) is observed in all eukaryotes and it is the site of protein folding, assembly of multi-subunit proteins, biosynthesis of lipids and sterols, and calcium storage. One major cellular stress is an augmented load of proteins targeted for secretion because the presence of too many unfolded proteins leads to an imbalance between the load of proteins entering the secretory pathway and the capacity of the ER to fold and process them, thereby leading to ER stress. To adapt to ER stress, a group of signal transduction proteins, termed the unfolded protein response (UPR), is activated. The UPR is mainly regulated by transmembrane ER-resident proteins such as inositol-requiring enzyme 1 (IRE1), PKR-like endoplasmic reticulum kinase (PERK), and activating transcription factor (ATF) 6. However, prolonged UPR leads to cell death via multiple apoptotic signaling cascades such as the CCAAT/enhancer-binding protein homologous protein (CHOP)-mediated pathway, IRE-1/tumor necrosis factor receptor-associated factor 2 (TRAF2)-mediated pathway, and Ca2+-associated signaling [1]. Although pharmacological modulators of ER stress usually protect cellular damage, literature on modulators is not always effective in establishing the link between ER-stress modulation and cellular damage. Furthermore, Varadarajan et al. demonstrated a new, evolutionarily conserved cellular stress response associated with reorganization of ER membrane that causes impairment of ER transport and function independently of the UPR [2].
Accumulated evidence demonstrates that ER stress is involved in the pathogenesis of protein misfolding disorders including neurodegenerative diseases (such as Parkinson’s and Alzheimer’s disease) and metabolic diseases (diabetes, cardiovascular disease, and non-alcoholic fatty liver). Therefore, the identification of pharmacological modulators is crucial for cytoprotection against cellular damage from ER stress. Based on previous reports, we have reviewed the protective effects of various drugs against cell damage caused by ER stress.

2. Cellular Aspects of ER-Stress and Metabolic Diseases

2.1. Diabetes Mellitus

Growing evidences support a critical role for activation of β-cell ER stress pathways in pathophysiology of diabetes [3]. Animal models of obesity and diabetes showed increased levels of ER stress, leading to insulin resistance and inflammatory responses [4]. Obesity has been reported to induce ER stress, which leads to the impairment of insulin signaling through hyperactivation of c-Jun N-terminal kinase (JNK)-mediated pathways [5]. Tersey et al. demonstrated that increased parameters of ER stress precede the onset of type 1 diabetes in isolated islets from prediabetic nonobese diabetic (NOD) mice [6]. Islet cells from 13 patients with type 1 diabetes revealed a partial ER stress response, including increased levels of CHOP [7]. Furthermore, PERK signaling is required to maintain endocrine function in pancreatic β-cells. Increased cell death and progressive diabetes mellitus with exocrine pancreatic insufficiency was observed in PERK knockout mice [8]. Similarly, conditional deletion of X-box binding protein 1 (XBP1) in pancreatic β-cells induced hyperglycemia and glucose intolerance resulting from reduced insulin secretion [9]. ER overload in β-cells induced ER stress which results in apoptosis via CHOP activation [10]. Targeted disruption of CHOP attenuated β-cell loss and delayed diabetes in the Akita mice, suggesting the pivotal role of the UPR in β-cell survival [10]. Thameem et al. reported that ATF6α polymorphisms are associated with type 2 diabetes in Pima Indians [11]. Elevations in the proinsulin/insulin ratio may be indicative of ER dysfunction in pancreatic β-cells, reflecting alterations in protein-folding and processing. Elevations in serum proinsulin/insulin ratio have been shown in patients with type 2 diabetes and those with new onset type 1 diabetes, while improvement in this ratio was reported following treatment with pioglitazone and IL-1β receptor antagonist therapy [3]. Glyburide treatment did not show further deleterious effects on ER stress or apoptosis of INS-1 cells in a glucotoxic condition [12].

2.2. Cardiovascular Diseases (CVD)

ER stress and UPR play major roles in the development and progression of CVD, including atherosclerosis, ischemic heart disease, and heart failure [13]. In ischemic-reperfusion injury, hypoxia and hypoglycemia caused by reduction of blood flow rapidly induce ER stress. Misfolded ER proteins are also caused by oxidative stress and alterations in the redox status of the ER in reperfusion of the affected tissues, when blood flow is recovered. Previous studies reported the protective roles of XBP-1 and ATF6 in ischemic/reperfusion injury, whereas activation of PERK/ATF4/CHOP pathway triggered apoptosis [14]. In apolipoprotein E-deficient mice, UPR markers were markedly increased in early intimal macrophages and in macrophage foam cells from advanced atherosclerotic lesions [15]. Saturated fatty acids, oxidized phospholipids, and oxidized low density lipoprotein (LDL) caused CD36-Toll-like receptor 2 (TLR2)-dependent apoptosis in ER-stressed macrophages, a key process in plaque necrosis [16].

2.3. Non-Alcoholic Fatty Liver Disease (NAFLD)

ER stress-mediated signal pathways have been shown to be associated with lipotoxicity, insulin resistance, inflammation, oxidative stress, and hepatic apoptosis, which are common properties of obesity and non-alcoholic fatty liver disease [17]. Elevated ER stress has been detected in liver of genetic and diet-induced non-alcoholic steatohepatitis (NASH) [18]. Furthermore, a variable degree of UPR activation was also documented in the liver of NAFLD or NASH patients [19]. Hepatic steatosis and lipogenesis are regulated by the PERK-eIF2α-ATF4 pathway [20]. Attenuated eIF2α in transgenic mouse liver was strongly correlated with suppression of adipogenesis-mediated regulators including peroxisome proliferate activated receptor-γ (PPAR-γ) and its upstream regulators, CCAAT/enhancer-binding proteins (C/EBP)-α and C/EBP-β [21]. ATF4-knockout mice showed protection from hypertriglyceridemia, diet-induced obesity, and hepatic steatosis [20]. In addition, the IRE1α-XBP1-mediated pathway is required for maintenance of hepatic lipid homeostasis under ER stress conditions. Hepatocyte-specific knock-out of IRE1α in mice led to the development of fatty liver after treatment with an ER stress inducer through modulation of transcriptional regulators such as PPAR-γ, C/EBP-β, C/EBP-δ, and triglyceride biosynthesis-related proteins [22]. ATF6α-deficient mice fed a high-fat diet showed a tendency toward a higher degree of hepatic steatosis in association with increased expression of SREBP1c [23]. Therefore, all three UPR sensors, including PERK, IRE1α, and ATF6α, are associated with hepatic steatosis and lipid metabolism in the liver [20].

3. Effects of Pharmacologic Modulators on ER Stress-Induced Cellular Damage

3.1. Rapamycin

A well-known mTOR (mammalian target of rapamycin) inhibitor, rapamycin suppresses ER stress through activation of autophagy in various cell types. A previous study showed that ER may be a source of the membranes used for the formation of autophagic vesicles [24]. ER stress is also involved in the essential process of the autophagic pathway, as shown in the polyglutamine-induced light chain 3 (LC3) conversion [25]. ER stress-mediated autophagy may play a critical role in disposal of misfolded proteins, which cannot be cleared by ER-related degradation, thereby contributing to maintaining ER homeostasis [26,27]. Therefore, ER stress-induced autophagy may have a protective role in cell apoptosis and stress at early stages, whereas prolonged ER stress may impair autophagy, consequently leading to cell death during the development of non-alcoholic fatty liver disease (NAFLD) [28]. Zhu et al. suggested that rapamycin protects the liver from hepatic ischemia and reperfusion injury (IRI) by activation of autophagy through inhibition of ER stress [29]. Wang et al. also demonstrated that restoration of autophagy by rapamycin attenuates hepatic ER stress and insulin resistance in high fructose-fed mice [30]. Rapamycin also ameliorates adipocyte dysfunction through restoration of the palmitate-induced ER stress/NFκB-mediated pathway via stimulation of autophagy [31]. Bachar-Wikstrom et al. showed the presence of crosstalk between ER stress and autophagy in a rodent model of diabetes [32]. They found that treatment of diabetic Akita mice with rapamycin prevented β-cell apoptosis and improved diabetes [32]. These reports suggest that activation of autophagy by rapamycin via mTOR inhibition may be an effective pharmacological modulator of ER stress. On the other hand, Kato et al. found that rapamycin attenuated ER stress-induced apoptosis via selective suppression of the IRE1-JNK signaling pathway [33]. Inhibition of mTOR with rapamycin repressed ER stress and the associated apoptosis during tunicamycin treatment in renal proximal tubular cells [34]. Hwang et al. reported that the inhibition of mTOR by rapamycin reversed ER stress-induced insulin resistance in L6 myotubes [35].

3.2. Chemical Chaperones

Exogenous chemical chaperones, which mimic endogenous chaperones, reinforce the adaptive capability of the ER through the improvement of ER folding capacity, the reduction of accumulation of misfolded proteins, and promotion of mutant proteins trafficking [36]. Chemical chaperones, such as 4-phenylbutyric acid (4-PBA), trimethylamine N-oxide dehydrate (TMAO), and dimethyl sulfoxide (DMSO), are low-molecular-weight compounds reported to improve ER capacity and move misfolded proteins [37]. 4-PBA alleviates ER stress and prevents adipocyte differentiation through suppression of UPR activation in 3T3-L1 cells and in the adipose tissue of high fat diet-fed C57BL/6 mice [38]. Tauroursodeoxycholic acid (TUDCA), a derivative of an endogenous bile acid, has been shown to abolish thapsigargin-induced ER stress markers and subsequently alleviates apoptosis in hepatocytes [39]. Treatment with PBA and TUDCA mitigates ER stress, which is associated with improvement of insulin sensitivity in liver, muscle, and adipose tissue in ob/ob mice [40]. Furthermore, TUDCA attenuates the progression of steatohepatitis by reducing ER stress in mice fed a methionine-choline-deficient (MCD)-diet [41]. These results suggest TUDCA as a therapeutic method for ER stress-mediated liver disease [18].

3.3. AMPK Activators

AMPK-activated protein kinase (AMPK) is a primary regulator of cellular and whole body energy homeostasis. Thus, AMPK has been considered a potential therapeutic target for metabolic diseases, such as type 2 diabetes. Furthermore, it also has been reported that activation of AMPK is able to attenuate ER stress, suggesting that AMPK can be a therapeutic target for the treatment of ER stress-mediated metabolic diseases [42]. AMPK activation by 5′-aminoimidazole-4-carboxymide-1-β-d-ribofuranoside (AICAR) significantly mitigates ER stress and improves the endothelium-dependent relaxation in isolated mouse aortae [43]. In addition, AICAR contributes to protection against hypoxic injury through reduction of ER stress in cardiomyocytes [44]. Metformin, an AMPK activator, is a widely used insulin sensitizer and has been reported to protect cells against ER stress induced by palmitate. Kim et al. described how the protective effect of metformin may be involved in the regulation of ER stress protein expression and palmitate-induced apoptosis in HepG2 cells, thereby providing a mechanism for how metformin may ameliorate hepatic insulin resistance under hyperlipidemic conditions [45]. Furthermore, metformin also exhibits protective effects on rat insulinoma cells through the suppression of palmitate-induced phosphorylation of eukaryotic initiation factor 2 α (eIF2α), JNK, and insulin receptor substrate-1 (IRS-1) suggesting that the β-cell protective effects of metformin in lipotoxicity may be associated with the suppression of ER stress [46]. In addition, metformin attenuates renal fibrosis through suppression of ER stress via the AMPK-mediated pathway. Kim et al. reported that metformin suppressed tunicamycin- or thapsigargin-induced ER stress and that knockdown of AMPK with siRNA blocked the effect of metformin in tubular HK-2 cells [47]. Furthermore, metformin ameliorates high-fat diet-induced endothelial dysfunction. Cheng et al. demonstrated the important role of AMPK-induced PPARδ activation in suppression of ER stress and protection of endothelial function in diabetic obese mice. Therefore, they suggested metformin as a therapeutic agent for treatment of cardiovascular disease [48]. Sen et al. found an association between mTOR activation, ER stress, and impaired contractile function in the mammalian heart, all of which were prevented by pretreatment with rapamycin or metformin [49]. These findings support a role for metformin in the reversal of various kinds of metabolic disorders through improvement of ER stress by an AMPK-dependent mechanism. ER stress has been reported to be elevated in adipose tissue of obese humans and is known to play an important role in the integration of pathways associated with inflammation and insulin signaling in chronic metabolic diseases [50]. Alhusaini et al. found that lipopolysaccharide (LPS), saturated fatty acids, and hyperglycemia significantly induced ER stress, which is alleviated by salicylate, a non-steroidal anti-inflammatory drug, in human adipocytes [51]. Salicylate also activates AMPK-dynamin-related protein 1 (Drp1) to inhibit mitochondrial ROS-associated ER stress, leading to prevention of inflammation and apoptosis in the vascular endothelium [52]. Moreover, salsalate, a prodrug of salicylate, lessens carrageenan-induced insulin resistance through inhibition of selenoprotein P via AMPK-mediated suppression of ER stress in hepatocytes [53].

3.4. Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists and Dipeptidyl Peptidase IV (DPP-IV) Inhibitors

GLP-1 is a 30-amino acid peptide hormone and an incretin derived from the transcription product of the proglucagon gene in intestinal epithelial endocrine L-cells [54]. GLP-1 appears to restore the glucose responsiveness of pancreatic β-cells and inhibit apoptosis of β-cells in freshly isolated human islets [55]. GLP-1 improves β-cell function through augmentation of mitochondrial mass and function in INS-1 rat insulinoma cells [56]. Moreover, GLP-1 also induces β-cell proliferation through transactivation of the epidermal growth factor receptor (EGFR) [57] and differentiation of pancreatic ductal cells into insulin-secreting cells [58]. The regulation of ER stress signaling by the GLP-1 pathway has also been consistently reported. Activation of the GLP-1 pathway by exenatide, a GLP-1 agonist, ameliorates ER stress via increased expression of activating transcription factor 4 (ATF4), thereby helping the cells to recover from ER stress-induced translational downregulation of insulin and improving cell survival in cultured β-cells in a PKA-dependent manner [59]. Exendin-4 protects β-cells against palmitate-induced ER stress and apoptosis through enhanced expression of cellular defense-mediated genes such as BiP, Bcl-2, and anti-apoptotic protein JunB [60]. Treatment of Akita mice, an animal model of ER stress-mediated diabetes, with exendin-4 can ameliorate ER stress-induced β-cell damage through a decrease in apoptotic cell death [61]. Prolonged high glucose and palmitate-induced ER stress and β-cell apoptosis are also attenuated by exendin-4 through regulation of SREBP1c and C/EBPβ transcription factors in INS-1 β-cells [62]. The impairment of sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) leads to Ca2+ release from the ER lumen, the accumulation of misfolded proteins in the ER lumen, and consequently, the imbalance of ER homeostasis [63]. Conversely, enhanced ER SERCA activity alleviates ER stress-induced apoptosis [64,65]. Exendin-4 attenuates high glucose-induced apoptosis, which is involved in the development of diabetic cardiomyopathy, through direct suppression of oxidative stress-induced ER stress via activation of SERCA2a in neonatal rat ventricular cardiomyocytes [66]. Lee et al. showed that exendin-4 increases SERCA2b to maintain ER homeostasis and ameliorate palmitic acid-induced ER stress through a SIRT1-dependent pathway in hepatocytes, which may be associated with improved insulin signaling and attenuation of steatosis [67]. Moreover, exendin-4 reduced hepatocyte steatosis and improved survival by restoring ER stress response and promoting autophagy [68]. Dipeptidyl peptidase (DPP)-4 is responsible for degradation of GLP-1 [69]. DPP4 inhibitor, vildagliptin, also increased pancreatic β-cell mass and improved ER stress, possibly through C/EBPβ degradation [70]. Another DPP4 inhibitor, sitagliptin, ameliorated hepatic steatosis, inflammation, and fibrosis in mice fed a MCD diet. In this report, sitagliptin ameliorated steatohepatitis by suppression of CD36 expression, NFκB activation, lipid peroxidation, and ER stress [71]. Moreover, we observed that the novel DPP4 inhibitor, gemigliptin, protected rat cardiomyocyte H9c2 cells against ER stress-induced apoptosis and inflammation through Akt/PERK/CHOP and IRE1α/JNK-p38-mediated pathways [72]. These findings suggest that activation of the GLP-1-mediated pathway by GLP-1 receptor agonists or DPP4 inhibitors may lead to beneficial effects on cardiometabolic diseases via amelioration of ER stress.

3.5. Peroxisome Proliferator-Activated Receptor (PPAR) Agonists

The PPAR-α agonist fenofibrate has been reported to protect against inflammatory injury and apoptosis through alleviation of ER stress via the IRE1α-XBP1-JNK-dependent pathway in the liver of an NAFLD mouse model, which is induced by feeding a high-calorie and high-cholesterol diet (HCD) [73]. Furthermore, fenofibrate treatment also restored palmitate-induced suppression of AMPK phosphorylation and adiponectin receptor 2 (AdipoR2) expression by attenuation of ER stress and inflammation in hepatocytes [74]. Lu et al. reported that fenofibrate recovered endothelium-dependent vasodilatation (EDV) induced by chronic high-fat diet (HFD) feeding through decreased ER stress and increased phosphorylation of endothelial nitric oxide synthase (eNOS) [75]. PPAR-γ agonist pioglitazone protects pancreatic islets by restoring sarco-endoplasmic reticulum Ca2+ ATPase 2b (SERCA2b) expression, thereby suppressing ER stress and leading to improvement of β-cell function and survival [76]. Yoshiuchi et al. demonstrated that pioglitazone treatment reduced ER stress, which may explain the insulin sensitizing effects of pioglitazone in the liver of ER stress-activated indicator (ERAI) transgenic mice [77]. In primary human myotubes, high stearoyl-coA desaturase 1 (SCD1) inducibility was related to low ER stress and inflammatory response to palmitate [78]. On the contrary, suppression of SCD1 increases palmitate-induced ER stress and apoptosis in insulin-secreting MIN6 cells [79]. Several PPAR-γ agonists suppress apoptosis through inhibition of palmitate-induced ER stress via up-regulation of SCD1 in RAW264.7, a murine macrophage cell line [80]. PPAR-δ agonist GW501516 improves palmitate-induced ER stress, inflammation, and insulin resistance in human and mouse skeletal muscle cells through activation of AMPK and inhibition of extracellular-signal-regulated kinas 1/2 (ERK1/2) [81]. Furthermore, GW501516 has been demonstrated to ameliorate the pro-inflammatory response in human cardiac AC16 cells exposed to palmitate [82]. Palomer et al. reported that PPAR-δ activation by GW501516 attenuated palmitate-induced ER stress by inducing autophagy in cardiomyocytes [83]. These findings suggest that agonists of PPARs might be useful therapeutic agents to correct ER stress-mediated metabolic abnormalities.

3.6. Angiotensin II Type 1 Receptor Blockers (ARBs)

Angiotensin II type 1 receptor blockers (ARBs) have been widely used to control blood pressure in patients with hypertension. Wu et al. demonstrated that valsartan, an ARB, can ameliorate ER stress via suppression of CHOP and the p53 upregulated modulator of apoptosis (Puma)-mediated pathway in cardiomyocytes of streptozotocin-induced diabetic rats [84]. Valsartan also has been shown to have a potential nephroprotective effect on contrast media-induced renal cell apoptosis by attenuation of ER stress, which is shown as suppression of glucose-regulated protein 78 (GRP78), ATF4, and CHOP [85]. Another ARB, losartan, protects human islets from hyperglycemia-induced ER stress through inhibition of the phospholipase C-inositol 1,4,5-triphosphate-Ca2+ (PLC-IP3-calcium)-mediated pathway, and thereby improves β-cell function, suggesting that the renin-angiotensin system plays an important role in human β-cell physiology [86]. Sukumaran et al. reported that olmesartan attenuated oxidative stress, inflammatory cytokines, and ER stress in rats with experimental autoimmune myocarditis (EAM) [87]. Guan et al. demonstrated that enhanced ER stress might be involved in cardiomyocyte apoptosis after aortic coarctation in rats [88]. They found that telmisartan significantly attenuated ER stress, thereby reducing cardiac left ventricular hypertrophy (LVH) and improving left ventricular function [88].

4. Conclusions

Current literature shows that various drugs protect cells or animals from the cellular damage induced by ER stress. These drugs directly modulate not only UPR and chaperones but also mediators, including AMPK, PPARs, and Akt, that can be the therapeutic targets for treatment of ER stress-mediated diseases (Table 1). Although our understanding of the pathophysiological role of ER stress in metabolic diseases has improved in recent years, further studies are needed to address several questions. (1) To what extent are the adaptive or proapoptotic pathways of the UPR involved in the pathophysiology of ER stress-mediated diseases? [89] (2) Is systemic suppression of ER stress good for health? (3) How can we deliver the agent to the specific target tissues? (4) How can we quickly and accurately screen agents that can ameliorate ER stress? To screen effective ER stress modulators, a CHOP promoter is fused with a fluorescence gene, and a stable cell line can be constructed with this cassette. ER stress modulators may be selected by measuring suppression of the ER stress-induced fluorescence signal.
In conclusion, research to identify compounds and therapeutic strategies to control ER stress may be essential for the treatment of ER stress-associated metabolic diseases. Furthermore, extensive clinical trials are required to evaluate more effective and safer drugs to modulate ER stress in humans.
Table
Table 1. Pharmacological modulators of ER stress with mediators. The arrows indicate regulation of signaling.
Table 1. Pharmacological modulators of ER stress with mediators. The arrows indicate regulation of signaling.
CategoryDrugMediatorEffect on DisordersReference
mTOR inhibitorsRapamycinAutophagy ↑NAFLD[6]
Hepatic ischemia[7]
Insulin resistance
(hepatocyte, skeletal myocytes)		[8,13]
Diabetes[10]
IRE1/JNK ↓Apoptosis (renal cell)[11,12]
Chemical chaperones4-PBAGRP78 ↓, CHOP ↓Adipogenesis[16]
TUDCACalcium efflux ↓Apoptosis (hepatocyte)[17]
eIF2α ↓, CHOP ↓Steatohepatitis[19]
AMPK activatorsMetforminAMPK ↑Renal fibrosis [26]
AMPK ↑, PPARδ ↑Vascular dysfunction[27]
eIF2α ↓, JNK ↓, IRS-1 ↓Apoptosis
(hepatocyte, endothelium)		[24,25,31]
Salicylate/SalsalateAMPK ↑Apoptosis (endothelium)[31]
Insulin resistance (hepatocyte)[32]
AICARAMPK ↑EDR (aortae)[22]
Cardiac hypoxic injury[23]
GLP-1 receptor agonists and DPP-4 inhibitorsExenatidePKA ↑, ATF4 ↑, BiP ↑, Bcl2 ↑, JunB ↑, SERCA ↑, Autophagy ↑Apoptosis (β-cell), NAFLD[38,39,46,47]
VildagliptinC/EBPβ ↓β-cell loss[49]
GemigliptinAkt/PERK/CHOP ↓,
IRE1α/JNK-p38 ↓		Apoptosis (cardiomyocyte)[51]
PPARs agonistsFenofibrateIRE1α/XBP1/JNK ↓,
AMPK ↑, eNOS ↑		NAFLD, EDV[52,53,54]
PioglitazoneSERCA ↑, SCD1 ↑β-cell dysfunction, Apoptosis (macrophage)[55,59]
GW1516AMPK ↑, ERK1/2 ↓Insulin resistance
(skeletal myocytes)		[60]
Autophagy ↑Cardiac hypertrophy[62]
ARBsValsartanPUMA ↓, GRP78 ↓Apoptosis
(cardiomyocyte, renal cell)		[63,64]
LosartanPLC-IP3-calcium ↓β-cell dysfunction[65]
OlmesartanGRP78 ↓, CHOP ↓Autoimmune myocarditis[66]
TelmisartanGRP78 ↓, CHOP ↓Cardiac hypertrophy[67]
IRE1, The inositol-requiring enzyme; JNK, c-Jun N-terminal kinases; TUDCA, Tauroursodeoxycholic acid; AICAR, 5-Aminoimidazole-4-carboxamide ribonucleotide; PKA, Protein kinase A; SERCA, The Sarco/Endoplasmic Reticulum Calcium ATPase; DPP-4, Dipeptidyl peptidase-4; eNOS, endothelial nitric oxide synthase; SCD1, Stearoyl-CoA desaturase-1; ERK, Extracellular signal-regulated kinases; mTOR, Mammalian target of rapamycin; AMPK, AMP-activated protein kinase; GLP-1, Glucagon-like peptide-1; PPAR, Peroxisome proliferator-activated receptor; ARB, Angiotensin II receptor blocker; NAFLD, Non-alcoholic fatty liver disease; EDV, Endothelium-dependent vasodilation; EDR, Endothelium-dependent relaxation.

Acknowledgments

The present work was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Korea (HI14C0133).

Author Contributions

Tae Woo Jung and Kyung Mook Choi drafted and approved the final version of the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Schroder, M.; Kaufman, R.J. ER stress and the unfolded protein response. Mutat. Res. 2005, 569, 29–63. [Google Scholar] [CrossRef] [PubMed]
  2. Varadarajan, S.; Bampton, E.T.; Smalley, J.L.; Tanaka, K.; Caves, R.E.; Butterworth, M.; Wei, J.; Pellecchia, M.; Mitcheson, J.; Gant, T.W.; et al. A novel cellular stress response characterised by a rapid reorganisation of membranes of the endoplasmic reticulum. Cell Death Differ. 2012, 19, 1896–1907. [Google Scholar] [CrossRef] [PubMed]
  3. Lipson, K.L.; Fonseca, S.G.; Ishigaki, S.; Nguyen, L.X.; Foss, E.; Bortell, R.; Rossini, A.A.; Urano, F. Regulation of insulin biosynthesis in pancreatic β cells by an endoplasmic reticulum-resident protein kinase IRE1. Cell Metab. 2006, 4, 245–254. [Google Scholar] [CrossRef] [PubMed]
  4. Delepine, M.; Nicolino, M.; Barrett, T.; Golamaully, M.; Lathrop, G.M.; Julier, C. EIF2AK3, encoding translation initiation factor 2-α kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat. Genet. 2000, 25, 406–409. [Google Scholar] [PubMed]
  5. Ozcan, U.; Cao, Q.; Yilmaz, E.; Lee, A.H.; Iwakoshi, N.N.; Ozdelen, E.; Tuncman, G.; Gorgun, C.; Glimcher, L.H.; Hotamisligil, G.S. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004, 306, 457–461. [Google Scholar] [CrossRef]
  6. Tersey, S.A.; Nishiki, Y.; Templin, A.T.; Cabrera, S.M.; Stull, N.D.; Colvin, S.C.; Evans-Molina, C.; Rickus, J.L.; Maier, B.; Mirmira, R.G. Islet β-cell endoplasmic reticulum stress precedes the onset of type 1 diabetes in the nonobese diabetic mouse model. Diabetes 2012, 61, 818–827. [Google Scholar] [CrossRef] [PubMed]
  7. Marhfour, I.; Lopez, X.M.; Lefkaditis, D.; Salmon, I.; Allagnat, F.; Richardson, S.J.; Morgan, N.G.; Eizirik, D.L. Expression of endoplasmic reticulum stress markers in the islets of patients with type 1 diabetes. Diabetologia 2012, 55, 2417–2420. [Google Scholar] [CrossRef] [PubMed]
  8. Harding, H.P.; Zeng, H.; Zhang, Y.; Jungries, R.; Chung, P.; Plesken, H.; Sabatini, D.D.; Ron, D. Diabetes mellitus and exocrine pancreatic dysfunction in perk−/− mice reveals a role for translational control in secretory cell survival. Mol. Cell 2001, 7, 1153–1163. [Google Scholar] [CrossRef]
  9. Laybutt, D.R.; Preston, A.M.; Akerfeldt, M.C.; Kench, J.G.; Busch, A.K.; Biankin, A.V.; Biden, T.J. Endoplasmic reticulum stress contributes to β cell apoptosis in type 2 diabetes. Diabetologia 2007, 50, 752–763. [Google Scholar] [CrossRef] [PubMed]
  10. Oyadomari, S.; Koizumi, A.; Takeda, K.; Gotoh, T.; Akira, S.; Araki, E.; Mori, M. Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. J. Clin. Investig. 2002, 109, 525–532. [Google Scholar] [CrossRef]
  11. Thameem, F.; Farook, V.S.; Bogardus, C.; Prochazka, M. Association of amino acid variants in the activating transcription factor 6 gene (ATF6) on 1q21-q23 with type 2 diabetes in Pima Indians. Diabetes 2006, 55, 839–842. [Google Scholar] [CrossRef] [PubMed]
  12. Kwon, M.J.; Chung, H.S.; Yoon, C.S.; Ko, J.H.; Jun, H.J.; Kim, T.K.; Lee, S.H.; Ko, K.S.; Rhee, B.D.; Kim, M.K.; et al. The Effects of glyburide on apoptosis and endoplasmic reticulum stress in INS-1 cells in a glucolipotoxic condition. Diabetes Metab. J. 2011, 35, 480–488. [Google Scholar] [CrossRef]
  13. Minamino, T.; Komuro, I.; Kitakaze, M. Endoplasmic reticulum stress as a therapeutic target in cardiovascular disease. Circ. Res. 2010, 107, 1071–1082. [Google Scholar] [CrossRef]
  14. Cnop, M.; Ladriere, L.; Hekerman, P.; Ortis, F.; Cardozo, A.K.; Dogusan, Z.; Flamez, D.; Boyce, M.; Yuan, J.; Eizirik, D.L. Selective inhibition of eukaryotic translation initiation factor 2α dephosphorylation potentiates fatty acid-induced endoplasmic reticulum stress and causes pancreatic β-cell dysfunction and apoptosis. J. Biol. Chem. 2007, 282, 3989–3997. [Google Scholar] [CrossRef] [PubMed]
  15. Zhou, J.; Lhotak, S.; Hilditch, B.A.; Austin, R.C. Activation of the unfolded protein response occurs at all stages of atherosclerotic lesion development in apolipoprotein E-deficient mice. Circulation 2005, 111, 1814–1821. [Google Scholar] [CrossRef] [PubMed]
  16. Seimon, T.A.; Nadolski, M.J.; Liao, X.; Magallon, J.; Nguyen, M.; Feric, N.T.; Koschinsky, M.L.; Harkewicz, R.; Witztum, J.L.; Tsimikas, S.; et al. Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress. Cell Metab. 2010, 12, 467–482. [Google Scholar] [CrossRef] [PubMed]
  17. Du, K.; Herzig, S.; Kulkarni, R.N.; Montminy, M. TRB3: A tribbles homolog that inhibits Akt/PKB activation by insulin in liver. Science 2003, 300, 1574–1577. [Google Scholar] [CrossRef] [PubMed]
  18. Passos, E.; Ascensao, A.; Martins, M.J.; Magalhaes, J. Endoplasmic reticulum stress response in non-alcoholic steatohepatitis: The possible role of physical exercise. Metabolism 2015, 64, 780–792. [Google Scholar] [CrossRef] [PubMed]
  19. Puri, P.; Mirshahi, F.; Cheung, O.; Natarajan, R.; Maher, J.W.; Kellum, J.M.; Sanyal, A.J. Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 2008, 134, 568–576. [Google Scholar] [CrossRef] [PubMed]
  20. Zhang, X.Q.; Xu, C.F.; Yu, C.H.; Chen, W.X.; Li, Y.M. Role of endoplasmic reticulum stress in the pathogenesis of nonalcoholic fatty liver disease. World J. Gastroenterol. 2014, 20, 1768–1776. [Google Scholar] [CrossRef] [PubMed]
  21. Oyadomari, S.; Harding, H.P.; Zhang, Y.; Oyadomari, M.; Ron, D. Dephosphorylation of translation initiation factor 2α enhances glucose tolerance and attenuates hepatosteatosis in mice. Cell Metab. 2008, 7, 520–532. [Google Scholar] [CrossRef] [PubMed]
  22. Zhang, K.; Wang, S.; Malhotra, J.; Hassler, J.R.; Back, S.H.; Wang, G.; Chang, L.; Xu, W.; Miao, H.; Leonardi, R.; et al. The unfolded protein response transducer IRE1α prevents ER stress-induced hepatic steatosis. EMBO J. 2011, 30, 1357–1375. [Google Scholar] [CrossRef] [PubMed]
  23. Usui, M.; Yamaguchi, S.; Tanji, Y.; Tominaga, R.; Ishigaki, Y.; Fukumoto, M.; Katagiri, H.; Mori, K.; Oka, Y.; Ishihara, H. Atf6α-null mice are glucose intolerant due to pancreatic β-cell failure on a high-fat diet but partially resistant to diet-induced insulin resistance. Metabolism 2012, 61, 1118–1128. [Google Scholar] [CrossRef] [PubMed]
  24. Shibutani, S.T.; Yoshimori, T. A current perspective of autophagosome biogenesis. Cell Res. 2014, 24, 58–68. [Google Scholar] [CrossRef] [PubMed]
  25. Kouroku, Y.; Fujita, E.; Tanida, I.; Ueno, T.; Isoai, A.; Kumagai, H.; Ogawa, S.; Kaufman, R.J.; Kominami, E.; Momoi, T. ER stress (PERK/eIF2α phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation. Cell Death Differ. 2007, 14, 230–239. [Google Scholar] [CrossRef] [PubMed]
  26. Qin, L.; Wang, Z.; Tao, L.; Wang, Y. ER stress negatively regulates AKT/TSC/mTOR pathway to enhance autophagy. Autophagy 2010, 6, 239–247. [Google Scholar] [CrossRef] [PubMed]
  27. Yorimitsu, T.; Klionsky, D.J. Endoplasmic reticulum stress: A new pathway to induce autophagy. Autophagy 2007, 3, 160–162. [Google Scholar] [CrossRef] [PubMed]
  28. Gonzalez-Rodriguez, A.; Mayoral, R.; Agra, N.; Valdecantos, M.P.; Pardo, V.; Miquilena-Colina, M.E.; Vargas-Castrillon, J.; Lo Iacono, O.; Corazzari, M.; Fimia, G.M.; et al. Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD. Cell Death Dis. 2014, 5, e1179. [Google Scholar] [CrossRef] [PubMed]
  29. Zhu, J.; Hua, X.; Li, D.; Zhang, J.; Xia, Q. Rapamycin attenuates mouse liver ischemia and reperfusion injury by inhibiting endoplasmic reticulum stress. Transplant. Proc. 2015, 47, 1646–1652. [Google Scholar] [CrossRef] [PubMed]
  30. Wang, H.; Sun, R.Q.; Zeng, X.Y.; Zhou, X.; Li, S.; Jo, E.; Molero, J.C.; Ye, J.M. Restoration of autophagy alleviates hepatic ER stress and impaired insulin signalling transduction in high fructose-fed male mice. Endocrinology 2015, 156, 169–181. [Google Scholar] [CrossRef] [PubMed]
  31. Yin, J.; Gu, L.; Wang, Y.; Fan, N.; Ma, Y.; Peng, Y. Rapamycin improves palmitate-induced ER stress/NF κB pathways associated with stimulating autophagy in adipocytes. Mediat. Inflamm. 2015, 2015, 272313. [Google Scholar]
  32. Bachar-Wikstrom, E.; Wikstrom, J.D.; Kaiser, N.; Cerasi, E.; Leibowitz, G. Improvement of ER stress-induced diabetes by stimulating autophagy. Autophagy 2013, 9, 626–628. [Google Scholar] [CrossRef] [PubMed]
  33. Kato, H.; Nakajima, S.; Saito, Y.; Takahashi, S.; Katoh, R.; Kitamura, M. mTORC1 serves ER stress-triggered apoptosis via selective activation of the IRE1-JNK pathway. Cell Death Differ. 2012, 19, 310–320. [Google Scholar] [CrossRef] [PubMed]
  34. Dong, G.; Liu, Y.; Zhang, L.; Huang, S.; Ding, H.F.; Dong, Z. mTOR contributes to ER stress and associated apoptosis in renal tubular cells. Am. J. Physiol. Ren. Physiol. 2015, 308, F267–F274. [Google Scholar] [CrossRef]
  35. Hwang, S.L.; Li, X.; Lee, J.Y.; Chang, H.W. Improved insulin sensitivity by rapamycin is associated with reduction of mTOR and S6K1 activities in L6 myotubes. Biochem. Biophys. Res. Commun. 2012, 418, 402–407. [Google Scholar] [CrossRef] [PubMed]
  36. Engin, F.; Hotamisligil, G.S. Restoring endoplasmic reticulum function by chemical chaperones: An emerging therapeutic approach for metabolic diseases. Diabetes Obes. Metab. 2010, 12, 108–115. [Google Scholar] [CrossRef] [PubMed]
  37. Welch, W.J.; Brown, C.R. Influence of molecular and chemical chaperones on protein folding. Cell Stress Chaperones 1996, 1, 109–115. [Google Scholar] [CrossRef]
  38. Basseri, S.; Lhotak, S.; Sharma, A.M.; Austin, R.C. The chemical chaperone 4-phenylbutyrate inhibits adipogenesis by modulating the unfolded protein response. J. Lipid Res. 2009, 50, 2486–2501. [Google Scholar] [CrossRef] [PubMed]
  39. Xie, Q.; Khaoustov, V.I.; Chung, C.C.; Sohn, J.; Krishnan, B.; Lewis, D.E.; Yoffe, B. Effect of tauroursodeoxycholic acid on endoplasmic reticulum stress-induced caspase-12 activation. Hepatology 2002, 36, 592–601. [Google Scholar] [CrossRef] [PubMed]
  40. Ozcan, U.; Yilmaz, E.; Ozcan, L.; Furuhashi, M.; Vaillancourt, E.; Smith, R.O.; Gorgun, C.Z.; Hotamisligil, G.S. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 2006, 313, 1137–1140. [Google Scholar] [CrossRef] [PubMed]
  41. Cho, E.J.; Yoon, J.H.; Kwak, M.S.; Jang, E.S.; Lee, J.H.; Yu, S.J.; Kim, Y.J.; Kim, C.Y.; Lee, H.S. Tauroursodeoxycholic acid attenuates progression of steatohepatitis in mice fed a methionine-choline-deficient diet. Dig. Dis. Sci. 2014, 59, 1461–1474. [Google Scholar] [CrossRef]
  42. Steinberg, G.R.; Kemp, B.E. AMPK in health and disease. Physiol. Rev. 2009, 89, 1025–1078. [Google Scholar] [CrossRef] [PubMed]
  43. Dong, Y.; Zhang, M.; Wang, S.; Liang, B.; Zhao, Z.; Liu, C.; Wu, M.; Choi, H.C.; Lyons, T.J.; Zou, M.H. Activation of AMP-activated protein kinase inhibits oxidized LDL-triggered endoplasmic reticulum stress in vivo. Diabetes 2010, 59, 1386–1396. [Google Scholar] [CrossRef] [PubMed]
  44. Terai, K.; Hiramoto, Y.; Masaki, M.; Sugiyama, S.; Kuroda, T.; Hori, M.; Kawase, I.; Hirota, H. AMP-activated protein kinase protects cardiomyocytes against hypoxic injury through attenuation of endoplasmic reticulum stress. Mol. Cell. Biol. 2005, 25, 9554–9575. [Google Scholar] [CrossRef] [PubMed]
  45. Kim, D.S.; Jeong, S.K.; Kim, H.R.; Chae, S.W.; Chae, H.J. Metformin regulates palmitate-induced apoptosis and ER stress response in HepG2 liver cells. Immunopharmacol. Immunotoxicol. 2010, 32, 251–257. [Google Scholar] [CrossRef] [PubMed]
  46. Simon-Szabo, L.; Kokas, M.; Mandl, J.; Keri, G.; Csala, M. Metformin attenuates palmitate-induced endoplasmic reticulum stress, serine phosphorylation of IRS-1 and apoptosis in rat insulinoma cells. PLoS ONE 2014, 9, e97868. [Google Scholar]
  47. Kim, H.; Moon, S.Y.; Kim, J.S.; Baek, C.H.; Kim, M.; Min, J.Y.; Lee, S.K. Activation of AMP-activated protein kinase inhibits ER stress and renal fibrosis. Am. J. Physiol. Ren. Physiol. 2015, 308, F226–F236. [Google Scholar] [CrossRef] [PubMed]
  48. Cheang, W.S.; Tian, X.Y.; Wong, W.T.; Lau, C.W.; Lee, S.S.; Chen, Z.Y.; Yao, X.; Wang, N.; Huang, Y. Metformin protects endothelial function in diet-induced obese mice by inhibition of endoplasmic reticulum stress through 5' adenosine monophosphate-activated protein kinase-peroxisome proliferator-activated receptor delta pathway. Arterioscler. Thromb. Vasc Biol. 2014, 34, 830–836. [Google Scholar] [CrossRef] [PubMed]
  49. Sen, S.; Kundu, B.K.; Wu, H.C.; Hashmi, S.S.; Guthrie, P.; Locke, L.W.; Roy, R.J.; Matherne, G.P.; Berr, S.S.; Terwelp, M.; et al. Glucose regulation of load-induced mTOR signaling and ER stress in mammalian heart. J. Am. Heart Assoc. 2013, 2, e004796. [Google Scholar] [CrossRef] [PubMed]
  50. Hotamisligil, G.S. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 2010, 140, 900–917. [Google Scholar] [CrossRef]
  51. Alhusaini, S.; McGee, K.; Schisano, B.; Harte, A.; McTernan, P.; Kumar, S.; Tripathi, G. Lipopolysaccharide, high glucose and saturated fatty acids induce endoplasmic reticulum stress in cultured primary human adipocytes: Salicylate alleviates this stress. Biochem. Biophys. Res. Commun. 2010, 397, 472–478. [Google Scholar] [CrossRef] [PubMed]
  52. Li, J.; Wang, Y.; Wen, X.; Ma, X.N.; Chen, W.; Huang, F.; Kou, J.; Qi, L.W.; Liu, B.; Liu, K. Pharmacological activation of AMPK prevents Drp1-mediated mitochondrial fission and alleviates endoplasmic reticulum stress-associated endothelial dysfunction. J. Mol. Cell. Cardiol. 2015, 86, 62–74. [Google Scholar] [CrossRef]
  53. Jung, T.W.; Lee, S.Y.; Hong, H.C.; Choi, H.Y.; Yoo, H.J.; Baik, S.H.; Choi, K.M. AMPK activator-mediated inhibition of endoplasmic reticulum stress ameliorates carrageenan-induced insulin resistance through the suppression of selenoprotein P in HepG2 hepatocytes. Mol. Cell. Endocrinol. 2014, 382, 66–73. [Google Scholar] [CrossRef] [PubMed]
  54. Kieffer, T.J.; Habener, J.F. The glucagon-like peptides. Endocr. Rev. 1999, 20, 876–913. [Google Scholar] [CrossRef] [PubMed]
  55. Farilla, L.; Bulotta, A.; Hirshberg, B.; Li Calzi, S.; Khoury, N.; Noushmehr, H.; Bertolotto, C.; di Mario, U.; Harlan, D.M.; Perfetti, R. Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology 2003, 144, 5149–5158. [Google Scholar] [CrossRef] [PubMed]
  56. Kang, M.Y.; Oh, T.J.; Cho, Y.M. Glucagon-like peptide-1 increases mitochondrial biogenesis and function in INS-1 Rat Insulinoma Cells. Endocrinol. Metab. (Seoul) 2015, 30, 216–220. [Google Scholar] [CrossRef] [PubMed]
  57. Buteau, J.; Foisy, S.; Joly, E.; Prentki, M. Glucagon-like peptide 1 induces pancreatic β-cell proliferation via transactivation of the epidermal growth factor receptor. Diabetes 2003, 52, 124–132. [Google Scholar] [CrossRef] [PubMed]
  58. Hui, H.; Wright, C.; Perfetti, R. Glucagon-like peptide 1 induces differentiation of islet duodenal homeobox-1-positive pancreatic ductal cells into insulin-secreting cells. Diabetes 2001, 50, 785–796. [Google Scholar] [CrossRef] [PubMed]
  59. Yusta, B.; Baggio, L.L.; Estall, J.L.; Koehler, J.A.; Holland, D.P.; Li, H.; Pipeleers, D.; Ling, Z.; Drucker, D.J. GLP-1 receptor activation improves β cell function and survival following induction of endoplasmic reticulum stress. Cell Metab. 2006, 4, 391–406. [Google Scholar] [CrossRef] [PubMed]
  60. Cunha, D.A.; Ladriere, L.; Ortis, F.; Igoillo-Esteve, M.; Gurzov, E.N.; Lupi, R.; Marchetti, P.; Eizirik, D.L.; Cnop, M. Glucagon-like peptide-1 agonists protect pancreatic β-cells from lipotoxic endoplasmic reticulum stress through upregulation of BiP and JunB. Diabetes 2009, 58, 2851–2862. [Google Scholar] [CrossRef] [PubMed]
  61. Yamane, S.; Hamamoto, Y.; Harashima, S.; Harada, N.; Hamasaki, A.; Toyoda, K.; Fujita, K.; Joo, E.; Seino, Y.; Inagaki, N. GLP-1 receptor agonist attenuates endoplasmic reticulum stress-mediated β-cell damage in Akita mice. J. Diabetes Investig. 2011, 2, 104–110. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Oh, Y.S.; Lee, Y.J.; Kang, Y.; Han, J.; Lim, O.K.; Jun, H.S. Exendin-4 inhibits glucolipotoxic ER stress in pancreatic beta cells via regulation of SREBP1c and C/EBPβ transcription factors. J. Endocrinol. 2013, 216, 343–352. [Google Scholar] [CrossRef] [PubMed]
  63. Berridge, M.J. The endoplasmic reticulum: A multifunctional signaling organelle. Cell Calcium 2002, 32, 235–249. [Google Scholar] [CrossRef] [PubMed]
  64. Zhang, J.; Li, Y.; Jiang, S.; Yu, H.; An, W. Enhanced endoplasmic reticulum SERCA activity by overexpression of hepatic stimulator substance gene prevents hepatic cells from ER stress-induced apoptosis. Am. J. Physiol. Cell Physiol. 2014, 306, C279–C290. [Google Scholar] [CrossRef] [PubMed]
  65. Fu, S.; Yang, L.; Li, P.; Hofmann, O.; Dicker, L.; Hide, W.; Lin, X.; Watkins, S.M.; Ivanov, A.R.; Hotamisligil, G.S. Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature 2011, 473, 528–531. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Younce, C.W.; Burmeister, M.A.; Ayala, J.E. Exendin-4 attenuates high glucose-induced cardiomyocyte apoptosis via inhibition of endoplasmic reticulum stress and activation of SERCA2a. Am. J. Physiol. Cell Physiol. 2013, 304, C508–C518. [Google Scholar] [CrossRef] [PubMed]
  67. Lee, J.; Hong, S.W.; Park, S.E.; Rhee, E.J.; Park, C.Y.; Oh, K.W.; Park, S.W.; Lee, W.Y. Exendin-4 attenuates endoplasmic reticulum stress through a SIRT1-dependent mechanism. Cell Stress Chaperones 2014, 19, 649–656. [Google Scholar] [CrossRef] [PubMed]
  68. Sharma, S.; Mells, J.E.; Fu, P.P.; Saxena, N.K.; Anania, F.A. GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy. PLoS ONE 2011, 6, e25269. [Google Scholar] [CrossRef] [PubMed]
  69. Barnett, A. DPP-4 inhibitors and their potential role in the management of type 2 diabetes. Int. J. Clin. Pract. 2006, 60, 1454–1470. [Google Scholar] [CrossRef]
  70. Shimizu, S.; Hosooka, T.; Matsuda, T.; Asahara, S.; Koyanagi-Kimura, M.; Kanno, A.; Bartolome, A.; Etoh, H.; Fuchita, M.; Teruyama, K.; et al. DPP4 inhibitor vildagliptin preserves β-cell mass through amelioration of endoplasmic reticulum stress in C/EBPB transgenic mice. J. Mol. Endocrinol. 2012, 49, 125–135. [Google Scholar] [CrossRef] [PubMed]
  71. Jung, Y.A.; Choi, Y.K.; Jung, G.S.; Seo, H.Y.; Kim, H.S.; Jang, B.K.; Kim, J.G.; Lee, I.K.; Kim, M.K.; Park, K.G. Sitagliptin attenuates methionine/choline-deficient diet-induced steatohepatitis. Diabetes Res. Clin. Pract. 2014, 105, 47–57. [Google Scholar] [CrossRef] [PubMed]
  72. Hwang, H.J.; Jung, T.W.; Ryu, J.Y.; Hong, H.C.; Choi, H.Y.; Seo, J.A.; Kim, S.G.; Kim, N.H.; Choi, K.M.; Choi, D.S.; et al. Dipeptidyl petidase-IV inhibitor (gemigliptin) inhibits tunicamycin-induced endoplasmic reticulum stress, apoptosis and inflammation in H9c2 cardiomyocytes. Mol. Cell. Endocrinol. 2014, 392, 1–7. [Google Scholar] [CrossRef] [PubMed]
  73. Zhang, N.; Lu, Y.; Shen, X.; Bao, Y.; Cheng, J.; Chen, L.; Li, B.; Zhang, Q. Fenofibrate treatment attenuated chronic endoplasmic reticulum stress in the liver of nonalcoholic fatty liver disease mice. Pharmacology 2015, 95, 173–180. [Google Scholar] [CrossRef] [PubMed]
  74. Rahman, S.M.; Qadri, I.; Janssen, R.C.; Friedman, J.E. Fenofibrate and PBA prevent fatty acid-induced loss of adiponectin receptor and pAMPK in human hepatoma cells and in hepatitis C virus-induced steatosis. J. Lipid Res. 2009, 50, 2193–2202. [Google Scholar] [CrossRef] [PubMed]
  75. Lu, Y.; Cheng, J.; Chen, L.; Li, C.; Chen, G.; Gui, L.; Shen, B.; Zhang, Q. Endoplasmic reticulum stress involved in high-fat diet and palmitic acid-induced vascular damages and fenofibrate intervention. Biochem. Biophys. Res. Commun. 2015, 458, 1–7. [Google Scholar] [CrossRef] [PubMed]
  76. Kono, T.; Ahn, G.; Moss, D.R.; Gann, L.; Zarain-Herzberg, A.; Nishiki, Y.; Fueger, P.T.; Ogihara, T.; Evans-Molina, C. PPAR-γ activation restores pancreatic islet SERCA2 levels and prevents β-cell dysfunction under conditions of hyperglycemic and cytokine stress. Mol. Endocrinol. 2012, 26, 257–271. [Google Scholar] [CrossRef] [PubMed]
  77. Yoshiuchi, K.; Kaneto, H.; Matsuoka, T.A.; Kasami, R.; Kohno, K.; Iwawaki, T.; Nakatani, Y.; Yamasaki, Y.; Shimomura, I.; Matsuhisa, M. Pioglitazone reduces ER stress in the liver: Direct monitoring of in vivo ER stress using ER stress-activated indicator transgenic mice. Endocr. J. 2009, 56, 1103–1111. [Google Scholar] [CrossRef] [PubMed]
  78. Peter, A.; Weigert, C.; Staiger, H.; Machicao, F.; Schick, F.; Machann, J.; Stefan, N.; Thamer, C.; Haring, H.U.; Schleicher, E. Individual stearoyl-coa desaturase 1 expression modulates endoplasmic reticulum stress and inflammation in human myotubes and is associated with skeletal muscle lipid storage and insulin sensitivity in vivo. Diabetes 2009, 58, 1757–1765. [Google Scholar] [CrossRef]
  79. Thorn, K.; Hovsepyan, M.; Bergsten, P. Reduced levels of SCD1 accentuate palmitate-induced stress in insulin-producing β-cells. Lipids Health Dis. 2010, 9, 108. [Google Scholar] [CrossRef] [PubMed]
  80. Ikeda, J.; Ichiki, T.; Takahara, Y.; Kojima, H.; Sankoda, C.; Kitamoto, S.; Tokunou, T.; Sunagawa, K. PPARγ agonists attenuate palmitate-induced ER stress through up-regulation of SCD-1 in macrophages. PLoS ONE 2015, 10, e0128546. [Google Scholar] [CrossRef]
  81. Salvado, L.; Barroso, E.; Gomez-Foix, A.M.; Palomer, X.; Michalik, L.; Wahli, W.; Vazquez-Carrera, M. PPARβ/δ prevents endoplasmic reticulum stress-associated inflammation and insulin resistance in skeletal muscle cells through an AMPK-dependent mechanism. Diabetologia 2014, 57, 2126–2135. [Google Scholar] [CrossRef] [PubMed]
  82. Alvarez-Guardia, D.; Palomer, X.; Coll, T.; Serrano, L.; Rodriguez-Calvo, R.; Davidson, M.M.; Merlos, M.; El Kochairi, I.; Michalik, L.; Wahli, W.; et al. PPARβ/δ activation blocks lipid-induced inflammatory pathways in mouse heart and human cardiac cells. Biochim. Biophys. Acta 2011, 1811, 59–67. [Google Scholar] [CrossRef] [PubMed]
  83. Palomer, X.; Capdevila-Busquets, E.; Botteri, G.; Salvado, L.; Barroso, E.; Davidson, M.M.; Michalik, L.; Wahli, W.; Vazquez-Carrera, M. PPARβ/δ attenuates palmitate-induced endoplasmic reticulum stress and induces autophagic markers in human cardiac cells. Int. J. Cardiol. 2014, 174, 110–118. [Google Scholar] [CrossRef] [PubMed]
  84. Wu, T.; Dong, Z.; Geng, J.; Sun, Y.; Liu, G.; Kang, W.; Zhang, Y.; Ge, Z. Valsartan protects against ER stress-induced myocardial apoptosis via CHOP/Puma signaling pathway in streptozotocin-induced diabetic rats. Eur. J. Pharm. Sci. 2011, 42, 496–502. [Google Scholar] [CrossRef] [PubMed]
  85. Peng, P.A.; Wang, L.; Ma, Q.; Xin, Y.; Zhang, O.; Han, H.Y.; Liu, X.L.; Ji, Q.W.; Zhou, Y.J.; Zhao, Y.X. Valsartan protects HK-2 cells from contrast media-induced apoptosis by inhibiting endoplasmic reticulum stress. Cell Biol. Int. 2015, 39, 1408–1417. [Google Scholar] [CrossRef] [PubMed]
  86. Madec, A.M.; Cassel, R.; Dubois, S.; Ducreux, S.; Vial, G.; Chauvin, M.A.; Mesnier, A.; Chikh, K.; Bosco, D.; Rieusset, J.; et al. Losartan, an angiotensin II type 1 receptor blocker, protects human islets from glucotoxicity through the phospholipase C pathway. FASEB. J. 2013, 27, 5122–5130. [Google Scholar] [CrossRef] [PubMed]
  87. Sukumaran, V.; Watanabe, K.; Veeraveedu, P.T.; Gurusamy, N.; Ma, M.; Thandavarayan, R.A.; Lakshmanan, A.P.; Yamaguchi, K.; Suzuki, K.; Kodama, M. Olmesartan, an AT1 antagonist, attenuates oxidative stress, endoplasmic reticulum stress and cardiac inflammatory mediators in rats with heart failure induced by experimental autoimmune myocarditis. Int. J. Biol. Sci. 2011, 7, 154–167. [Google Scholar] [CrossRef] [PubMed]
  88. Guan, H.S.; Shangguan, H.J.; Shang, Z.; Yang, L.; Meng, X.M.; Qiao, S.B. Endoplasmic reticulum stress caused by left ventricular hypertrophy in rats: Effects of telmisartan. Am. J. Med. Sci. 2011, 342, 318–323. [Google Scholar] [CrossRef]
  89. Chan, J.Y.; Cooney, G.J.; Biden, T.J.; Laybutt, D.R. Differential regulation of adaptive and apoptotic unfolded protein response signalling by cytokine-induced nitric oxide production in mouse pancreatic beta cells. Diabetologia 2011, 54, 1766–1776. [Google Scholar] [CrossRef] [PubMed]

Share and Cite

MDPI and ACS Style

Jung, T.W.; Choi, K.M. Pharmacological Modulators of Endoplasmic Reticulum Stress in Metabolic Diseases. Int. J. Mol. Sci. 2016, 17, 192. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17020192

AMA Style

Jung TW, Choi KM. Pharmacological Modulators of Endoplasmic Reticulum Stress in Metabolic Diseases. International Journal of Molecular Sciences. 2016; 17(2):192. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17020192

Chicago/Turabian Style

Jung, Tae Woo, and Kyung Mook Choi. 2016. "Pharmacological Modulators of Endoplasmic Reticulum Stress in Metabolic Diseases" International Journal of Molecular Sciences 17, no. 2: 192. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17020192

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop