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

Usui, Masahiro; Yamaguchi, Suguru; Tanji, Yasuhiro; Tominaga, Ryu; Ishigaki, Yasushi; Fukumoto, Manabu; Katagiri, Hideki; Mori, Kazutoshi; Oka, Yoshitomo; Ishihara, Hideharu

doi:10.1016/j.metabol.2012.01.004

Cited by 124 publications

(94 citation statements)

References 40 publications

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“…Pancreatic β-cells suffered from ER stress in the Atf6α-deficient mice. 40) These findings suggest that the three major UPR pathways are involved in ER stress of pancreatic β-cells.…”

Section: Diabetesmentioning

confidence: 89%

ER Stress and Disease: Toward Prevention and Treatment

Kaneko

Imaizumi

Saito

et al. 2017

Biological & Pharmaceutical Bulletin

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Secretory and membrane proteins are synthesized in ribosomes, then mature in the endoplasmic reticulum (ER), but if ER function is impaired, immature defective proteins accumulate in the ER. This situation is called ER stress: in response, a defensive mechanism called the unfolded protein response (UPR) is activated in cells to reduce the defective proteins. During the UPR, the ER transmembrane sensor molecules inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6), and RNA-dependent protein kinase (PKR)-like ER kinase (PERK) are activated, stress signals are transduced to the outside of the ER, and various cell responses, including gene induction, occur. In ER-associated degradation (ERAD), one type of UPR, defective proteins are eventually expelled from the ER and degraded in the cytoplasm through the ubiquitin proteasome system. Since ER stress has been reported to have relationships with neurodegenerative diseases, diabetes, metabolic syndromes, and cancer, it is the focus of increased attention from the perspectives of elucidating pathogenic mechanisms, and in the development of therapeutics.

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“…Pancreatic β-cells suffered from ER stress in the Atf6α-deficient mice. 40) These findings suggest that the three major UPR pathways are involved in ER stress of pancreatic β-cells.…”

Section: Diabetesmentioning

confidence: 89%

ER Stress and Disease: Toward Prevention and Treatment

Kaneko

Imaizumi

Saito

et al. 2017

Biological & Pharmaceutical Bulletin

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“…/ mice developed hepatic steatosis and glucose intolerance in association with increased expression of SREBP-1c (54). On the other hand, overexpression of a functionally active nuclear fragment of ATF6 in zebrafish caused fatty liver (55), suggesting that fine-tuning of ATF6 may be important to prevent liver steatosis.…”

Section: Er Stress and The Uprmentioning

confidence: 99%

The role of ER stress in lipid metabolism and lipotoxicity

Han

Kaufman

2016

Journal of Lipid Research

504

372

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extremely high Ca 2+ concentration (1), which is maintained by the active transport function of the sarco/ER calcium ATPase (SERCA) (2). Many ER chaperone proteins and enzymes depend on higher Ca 2+ levels to facilitate protein folding and maturation (3). Therefore, maintaining ER homeostasis is essential for proper protein production and cell function. Homeostasis in the ER is disrupted by a number of insults, including pharmacological perturbation, genetic mutation of ER chaperones or their client proteins, elevated expression of proteins that transit the endomembrane system, viral infection, alterations in Ca 2+ or redox status, and limited or excessive available nutrients such as lipids. The accumulation of unfolded or misfolded proteins in the ER lumen activates a set of intracellular signaling pathways known as the unfolded protein response (UPR) (4, 5). The UPR regulates the quantity of ER driven by synthesis of lipids (6) and protein components of the ER to accommodate fluctuating demands on protein folding and other ER functions in response to different physiological and pathological conditions.The ER is also the major site for the synthesis of sterols and phospholipids that constitute the bulk of the lipid components of all biological membranes. In addition, many enzymes and regulatory proteins involved in lipid metabolism reside in the ER. The ER, therefore, plays an essential role in controlling membrane lipid composition (7) and membrane lipid homeostasis in all cell types. Fat The endoplasmic reticulum (ER) is a central organelle where proteins destined for the cell surface and the endomembrane system enter the secretory pathway. Once inside the ER lumen, newly synthesized polypeptides fold into their three-dimensional structures, assemble into higher order multimeric complexes, and are subject to posttranslational modifications such as glycosylation, hydroxylation, lipidation, and disulfide formation. The ER contains an Abbreviations: ACC, acetyl-CoA carboxylase; ATF4, activating transcription factor 4; ATF6, activating transcription factor 6; BiP, immunoglobulin heavy-chain binding protein; CHOP, C/EBP homologous protein; eIF2, eukaryotic translation initiation factor 2; ER, endoplasmic reticulum; ERAD, ER-associated degradation; FXR, farnesoid X receptor; GADD34, growth arrest and DNA damage-inducible protein 34; HFD, high-fat diet; HFrD, high-fructose diet; IRE1, inositol-requiring enzyme 1; 4-PBA, 4-phenylbutyric acid; PERK, the double-stranded RNAactivated protein kinase-like eukaryotic initiation factor 2 kinase; ROS, reactive oxygen species; SCD1, stearoyl-CoA desaturase 1; SERCA, sarco/ endoplasmic reticulum calcium ATPase; SFA, saturated fatty acid; S1P, serine protease site-1; S2P, metalloprotease site-2; SREBP, sterol regulatory element-binding protein; TUDCA, tauroursodeoxycholic acid; UPR, unfolded protein response; VLDLR, VLDL receptor; XBP1, X-box binding protein 1; Xbp1s, transcriptionally active form of X-box binding protein 1.

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“…Single-nucleotide polymorphisms exist in a functionally important region of the ATF6α gene that is associated with type 2 diabetes in a population of Pima Indians (Thameem et al 2006), Dutch Caucasians (Meex et al 2007), and Chinese (Gonzalez-Rodriguez et al 2014). Moreover, high-fat diet (HFD)-fed Atf6α −/− mice displayed glucose intolerance, blunted insulin secretion, and reduced pancreatic insulin content due to β-cell failure (Usui et al 2012). In type 1 diabetes, there is a progressive loss of ATF6α expression before the onset of diabetes in nonobese diabetic (NOD) mice as well as in pancreata from type 1 diabetic patients, suggesting that ATF6α protects β cells (Engin et al 2013).…”

Section: Atf6αmentioning

confidence: 99%

Physiological/pathological ramifications of transcription factors in the unfolded protein response

2017

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Numerous environmental, physiological, and pathological insults disrupt protein-folding homeostasis in the endoplasmic reticulum (ER), referred to as ER stress. Eukaryotic cells evolved a set of intracellular signaling pathways, collectively termed the unfolded protein response (UPR), to maintain a productive ER protein-folding environment through reprogramming gene transcription and mRNA translation. The UPR is largely dependent on transcription factors (TFs) that modulate expression of genes involved in many physiological and pathological conditions, including development, metabolism, inflammation, neurodegenerative diseases, and cancer. Here we summarize the current knowledge about these mechanisms, their impact on physiological/pathological processes, and potential therapeutic applications.

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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

Cited by 124 publications

References 40 publications

ER Stress and Disease: Toward Prevention and Treatment

ER Stress and Disease: Toward Prevention and Treatment

The role of ER stress in lipid metabolism and lipotoxicity

Physiological/pathological ramifications of transcription factors in the unfolded protein response

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