IRE1α-XBP1 is a novel branch in the transcriptional regulation of Ucp1 in brown adipocytes

Asada, Rie; Kanemoto, Soshi; Matsuhisa, Koji; Hino, Kazunori; Cui, Min; Cui, Xiang; Kaneko, Masayuki; Imaizumi, Kazunori

doi:10.1038/srep16580

Cited by 27 publications

(21 citation statements)

References 54 publications

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“…As plasma IL-6 levels are increased acutely after CLP and remain elevated after 10 days, this mechanism may also explain in part the browning of WAT during sepsis. In the current model, the sepsis-induced increase in ER stress precedes WAT browning and is consistent with data suggesting that increased ER stress governs the transcriptional induction of UCP-1 in brown adipocytes (5).…”

Section: R395supporting

confidence: 91%

Inability to replete white adipose tissue during recovery phase of sepsis is associated with increased autophagy, apoptosis, and proteasome activity

Crowell

Soybel

Lang

2017

American Journal of Physiology-Regulatory, Integrative and Comp

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Adipose tissue is an important energy depot and endocrine organ, and the degree of adiposity impacts the host response to infection. However, little is known regarding the mechanisms by which white adipose tissue (WAT) is lost acutely and then restored after the resolution of sepsis. Therefore, the signaling pathways governing protein synthesis, autophagy, apoptosis, and the ubiquitin-proteasome were investigated to identify potential mechanisms mediating the acute (24 h) loss of WAT after cecal ligation and puncture as well as the failure to replenish WAT during recovery (). While whole body fat mass was decreased equally in pair-fed control and septic mice at 5 days after cecal ligation and puncture, fat mass remained 35% lower in septic mice at During sepsis-recovery, protein synthesis in epididymal WAT was increased compared with control values, and this increase was associated with an elevation in eukaryotic translation initiation factor (eIF)2Bε but no change in mammalian target of rapamycin complex 1 activity (eIF4E-binding protein-1 or S6 kinase 1 phosphorylation). Protein breakdown was increased during sepsis-recovery, as evidenced by the elevation in ubiquitin-proteasome activity. Moreover, indexes of autophagy (light chain 3B-II, autophagy-related protein 5/12, and beclin) were increased during sepsis-recovery and associated with increased AMP-activated kinase-dependent Ser-phosphorylated Unc-51-like autophagy activating kinase-1. Apoptosis was increased, as suggested by the increased cleavage of caspase-3 and poly(ADP-ribose) polymerase. These changes were associated with increased inflammasome activity (increased NLR family, pyrin domain containing 3; TMS1; and caspase-1 cleavage) and the endoplasmic reticulum stress response (increased eIF2α and activating transcription factor-4) and browning (uncoupling protein-1) in epididymal WAT. Our data suggest that WAT stores remain depleted during recovery from sepsis due to sustained inflammation and elevations in protein and cellular degradation, despite the increase in protein synthesis.

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Section: R395supporting

confidence: 91%

Inability to replete white adipose tissue during recovery phase of sepsis is associated with increased autophagy, apoptosis, and proteasome activity

Crowell

Soybel

Lang

2017

American Journal of Physiology-Regulatory, Integrative and Comp

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“…The activation of IRE1 induces site-speciﬁc splicing of XBP1 mRNA. The genes upregulated by XBP1 mRNA improve clearance of unfolded proteins and are associated with the increase of pro-survival functions, [43] besides, XBP1 binds to the endoplasmic reticulum stress elements (ERSE), that promote the expression of FGF21 [44], [45]. When all these protective steps are unable to control the injuring stimulus, intracellular death pathways are activated [46], [47].…”

Section: Fgf21 and Cellular Oxidative Stressmentioning

confidence: 99%

Fibroblast growth factor 21 and its novel association with oxidative stress

et al. 2017

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Fibroblast growth factor 21 (FGF21) is an endocrine-member of the FGF family. It is synthesized mainly in the liver, but it is also expressed in adipose tissue, skeletal muscle, and many other organs. It has a key role in glucose and lipid metabolism, as well as in energy balance. FGF21 concentration in plasma is increased in patients with obesity, insulin resistance, and metabolic syndrome. Recent findings suggest that such increment protects tissue from an increased oxidative stress environment. Different types of physical stress, such as strenuous exercising, lactation, diabetic nephropathy, cardiovascular disease, and critical illnesses, also increase FGF21 circulating concentration. FGF21 is now considered a stress-responsive hormone in humans. The discovery of an essential response element in the FGF21 gene, for the activating transcription factor 4 (ATF4), involved in the regulation of oxidative stress, and its relation with genes such as NRF2, TBP-2, UCP3, SOD2, ERK, and p38, places FGF21 as a key regulator of the oxidative stress cell response. Its role in chronic diseases and its involvement in the treatment and follow-up of these diseases has been recently the target of new studies. The diminished oxidative stress through FGF21 pathways observed with anti-diabetic therapy is another clue of the new insights of this hormone.

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“…However, UPR is also involved in processes having little to do with protein folding. For example, XBP1 has been shown to be required for cardiac myogenesis, hepatogenesis, plasma cell differentiation, the development of secretory tissues, cytokines production, memory formation, glucose homeostasis, and thermogenesis [45][46][47][48][49][50][51][52]. Recently, XBP1 was found to suppress lipogenic gene expression and reduce hepatic triglyceride and diacylglycerol content in the livers of obese mice [53].…”

Section: Discussionmentioning

confidence: 99%

Growth hormone activates X-box binding protein 1 in a sexually dimorphic manner through the extracellular signal-regulated protein kinase and CCAAT/enhancer-binding protein β pathway in rat liver

et al. 2020

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Growth hormone (GH) has multiple physiological roles, acting on many organs. In order to investigate its roles in rat liver, we tried to identify novel genes whose transcription was regulated by GH. We identified X-box binding protein 1 (Xbp1) as a candidate gene. XBP1 is a key transcription factor activated in response to endoplasmic reticulum (ER) stress. The purpose of this study was to investigate the mode of action of GH on XBP1, including the relation with ER stress, sexdependent expression of the mRNA, and the signaling pathway. Intravenous administration of GH rapidly and transiently increased Xbp1 mRNA in hypophysectomized rat livers. Neither phosphorylated inositol-requiring-1α (IRE1α) nor phosphorylated PKR-like ER kinase (PERK) increased, suggesting that Xbp1 expression is induced by an ER stressindependent mechanism. The active form of XBP1(S) protein was increased by GH administration and was followed by an increased ER-associated dnaJ protein 4 (ERdj4) mRNA level. XBP1(S) protein levels were predominantly identified in male rat livers with variations among individuals similar to those of phosphorylated signal transducer and activator of transcription 5B (STAT5B), suggesting that XBP1(S) protein levels are regulated by the sex-dependent secretary pattern of GH. The GH signaling pathway to induce Xbp1 mRNA was examined in rat hepatoma H4IIE cells. GH induced the phosphorylation of CCAAT/enhancer-binding protein β (C/EBPβ) following extracellular signal-regulated protein kinase (ERK) phosphorylation. Taken together, the results indicated that XBP1 is activated by GH in rat liver in a sexually dimorphic manner via ERK and C/ EBPβ pathway.

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IRE1α-XBP1 is a novel branch in the transcriptional regulation of Ucp1 in brown adipocytes

Cited by 27 publications

References 54 publications

Inability to replete white adipose tissue during recovery phase of sepsis is associated with increased autophagy, apoptosis, and proteasome activity

Inability to replete white adipose tissue during recovery phase of sepsis is associated with increased autophagy, apoptosis, and proteasome activity

Fibroblast growth factor 21 and its novel association with oxidative stress

Growth hormone activates X-box binding protein 1 in a sexually dimorphic manner through the extracellular signal-regulated protein kinase and CCAAT/enhancer-binding protein β pathway in rat liver

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