Endoplasmic Reticulum (ER) Stress and Endocrine Disorders

Ariyasu, Daisuke; Yoshida, Hiderou; Hasegawa, Yukihiro

doi:10.3390/ijms18020382

Cited by 95 publications

(68 citation statements)

References 198 publications

(211 reference statements)

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“…Changes in ATF6 expression and activity have been described in multiple human disorders, including the eye disease achromatopsia, myocardial infarction, stroke, amyloidosis, and a number of cancers (Ariyasu et al, 2017; Chiang et al, 2012; Manie et al, 2014; Plate et al, 2016; Urra et al, 2016; Zhou and Tabas, 2013). The finding that atf6 —/— mice have a higher incidence of neuronal cell death upon brain ischemia compared with wild-type mice argues for a protective effect of ATF6 (Yoshikawa et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

The UPR Activator ATF6 Responds to Proteotoxic and Lipotoxic Stress by Distinct Mechanisms

et al. 2018

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The unfolded protein response (UPR) is induced by proteotoxic stress of the endoplasmic reticulum (ER). Here we report that ATF6, a major mammalian UPR sensor, is also activated by specific sphingolipids, dihydrosphingosine (DHS) and dihydroceramide (DHC). Single mutations in a previously undefined transmembrane domain motif that we identify in ATF6 incapacitate DHS/DHC activation while still allowing proteotoxic stress activation via the luminal domain. ATF6 thus possesses two activation mechanisms: DHS/DHC activation and proteotoxic stress activation. Reporters constructed to monitor each mechanism show that phenobarbital-induced ER membrane expansion depends on transmembrane domain-induced ATF6. DHS/DHC addition preferentially induces transcription of ATF6 target lipid biosynthetic and metabolic genes over target ER chaperone genes. Importantly, ATF6 containing a luminal achromatopsia eye disease mutation, unresponsive to proteotoxic stress, can be activated by fenretinide, a drug that upregulates DHC, suggesting a potential therapy for this and other ATF6-related diseases including heart disease and stroke.

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Section: Discussionmentioning

confidence: 99%

The UPR Activator ATF6 Responds to Proteotoxic and Lipotoxic Stress by Distinct Mechanisms

et al. 2018

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“…During physiological conditions, such as stem cell differentiation and proliferation, a certain level of ER stress may be required to compensate for increased cellular demands (Matsuzaki et al, ). However, pathophysiological conditions, such as obesity and diabetes, may induce ER stress as well (Ariyasu, Yoshida, & Hasegawa, ; Januszyk et al, ; Pagliassotti, Kim, Estrada, Stewart, & Gentile, ) and studies in mouse models have shown that both of these metabolic conditions may negatively affect stem cell behavior (Januszyk et al, ; D. Wu, Ren, Pae, Han, & Meydani, ). The mechanisms through which obesity, in the absence of comorbidity, affects stem cell functions, and BM‐MSCs in particular, are currently not fully understood, despite the presence of accumulating evidence indicating the importance of ER stress in the dysfunction of stem cells in obesity (Pagliassotti et al, ).…”

Section: Discussionmentioning

confidence: 99%

Bone marrow mesenchymal stem cell donors with a high body mass index display elevated endoplasmic reticulum stress and are functionally impaired

Ulum

Teker

Sarıkaya

et al. 2018

Journal Cellular Physiology

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Bone marrow mesenchymal stem cells (BM-MSCs) are promising candidates for regenerative medicine purposes. The effect of obesity on the function of BM-MSCs is currently unknown. Here, we assessed how obesity affects the function of BM-MSCs and the role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) therein. BM-MSCs were obtained from healthy donors with a normal (<25) or high (>30) body mass index (BMI). High-BMI BM-MSCs displayed severely impaired osteogenic and diminished adipogenic differentiation, decreased proliferation rates, increased senescence, and elevated expression of ER stress-related genes ATF4 and CHOP. Suppression of ER stress using tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyrate (4-PBA) resulted in partial recovery of osteogenic differentiation capacity, with a significant increase in the expression of ALPL and improvement in the UPR. These data indicate that BMI is important during the selection of BM-MSC donors for regenerative medicine purposes and that application of high-BMI BM-MSCs with TUDCA or 4-PBA may improve stem cell function. However, whether this improvement can be translated into an in vivo clinical advantage remains to be assessed.

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“…PKR-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6), and inositol requirement 1 (IRE1), are well-characterized ER membrane-located proteins which sense ER stress. In the presence of ER stress, PERK is activated by trans-autophosphorylation, ATF6 activates expression of the ER chaperone immunoglobulin heavy-chain binding protein (BiP), and IRE1 activates splicing of X-box binding protein 1 ( Xbp1 ) mRNA via the PERK, ATF6, and IRE1 pathways, respectively (Ariyasu et al, 2017; Yoshida, 2007). PERK phosphorylation can be detected by immunoblotting, as phosphorylated PERK is associated with a mobility shift during SDS-PAGE (Harding et al, 1999).…”

Section: Resultsmentioning

confidence: 99%

“…These data suggest that Δ3 GH can activate the three major ER stress pathways in vivo; however, activation of these ER stress pathways is not sufficiently strong to cause somatotroph apoptosis, since no apoptotic cells were detected by TUNEL assay, as described above (Fig 3B), and no caspase-3 activation was detected in Gh wtGH1/Δ3GH1 pituitary glands by immunoblotting (Fig 4A). In other established ER stress-related endocrine diseases, apoptosis is required to cause organ dysfunction (Ariyasu et al, 2017; Fonseca et al, 2010; Hayashi et al, 2009; Oyadomari et al, 2002; Yoshida, 2007). These data suggest that Δ3 GH-mediated ER stress is not likely to be causally related to the growth retardation in Gh wtGH1/Δ3GH1 mice.…”

Section: Resultsmentioning

confidence: 99%

Decreased Activity of theGhrhrandGhPromoters Causes Dominantly Inherited GH Deficiency

Ariyasu¹,

Kubo²,

Higa³

et al. 2019

Preprint

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26Isolated growth hormone deficiency type II (IGHD2) is mainly caused by 27 heterozygous splice-site mutations in intron 3 of the GH1 gene. A dominant negative 28 effect of the mutant growth hormone (GH) lacking exon 3 on wild-type GH secretion has 29 been proposed; however, the molecular mechanisms involved are elusive. To uncover 30 the molecular systems underlying GH deficiency in IGHD2, we established IGHD2 31 model mice, which carry both wild-type and mutant copies of the human GH1 gene, 32replacing each of the endogenous mouse Gh loci. Our IGHD2 model mice exhibited 33 growth retardation associated with intact cellular architecture and mildly activated ER 34 stress in the pituitary gland, caused by decreases in the growth hormone releasing 35 hormone receptor (Ghrhr) and Gh gene promoter activities. Decreases in Ghrhr and Gh 36 promoter activities were likely caused by reduced levels of nuclear CREB3L2, which 37 was demonstrated to stimulate the activity of the Ghrhr and Gh promoters. This is the 38 first in vivo study revealing a novel molecular mechanism of GH deficiency in IGHD2, 39 representing a new paradigm, differing from widely accepted models. 40 41 Key Words: dominant negative effect/ endoplasmic reticulum stress/ growth hormone/ 42 growth hormone releasing hormone receptor/ isolated growth hormone deficiency type 43 II 44 45 22-kDa wild-type GH protein; however, the mutant GH1 allele transcript generates a 52 17.5-kDa exon 3 deletion-mutant GH (Δ3 GH), as a result of in-frame skipping of exon 3. 53The fact that patients harboring a deletion in one GH1 allele exhibit normal stature 54indicates that a single wild-type GH1 allele is sufficient to produce normal levels of 55 wild-type GH secretion (Akinci et al, 1992); however, patients with IGHD2 have low 56 serum concentrations of wild-type GH, despite having a wild-type GH1 allele. Thus, it 57 has been suggested that Δ3 GH exerts a dominant negative effect on wild-type GH 58 secretion; however, the precise molecular mechanisms involved have remained elusive 59 for more than 20 years. 60 3 Several in vitro studies have demonstrated that Δ3 GH is not secreted 61 extracellularly (Graves et al, 2001; Iliev et al, 2005; Kannenberg et al, 2007; Mullis et al, 62 2002; Salemi et al, 2006), suggesting that the dominant negative effect of Δ3 GH is 63 exerted within somatotropic cells of the pituitary, where GH is generated. Generally, 64 mutant proteins exert dominant negative effects on secretory pathways of wild-type 65 factors at the protein level (Deladoey et al, 2001; Ito et al, 1999; Jacobson et al, 1997), 66 which has led many researchers to focus on wild-type and Δ3 GH protein interactions, 67 such as heterodimer formation; however, no study has yet demonstrated definitive 68 evidence of heterodimers comprising wild-type and Δ3 GH proteins. At present, it is 69 widely accepted that Δ3 GH itself is not harmful to somatotroph (Graves et al, 2001), 70 and that wild-type GH contributes to the degradation of Δ3 GH via protein interactions, 71 leading ...

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Endoplasmic Reticulum (ER) Stress and Endocrine Disorders

Cited by 95 publications

References 198 publications

The UPR Activator ATF6 Responds to Proteotoxic and Lipotoxic Stress by Distinct Mechanisms

The UPR Activator ATF6 Responds to Proteotoxic and Lipotoxic Stress by Distinct Mechanisms

Bone marrow mesenchymal stem cell donors with a high body mass index display elevated endoplasmic reticulum stress and are functionally impaired

Decreased Activity of theGhrhrandGhPromoters Causes Dominantly Inherited GH Deficiency

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