Sequestration of fatty acids in triglycerides prevents endoplasmic reticulum stress in an in vitro model of cardiomyocyte lipotoxicity

Bosma, Madeleen; Dapito, Dianne H.; Drosatos-Tampakaki, Zoi; Ni, Hemin; Huang, Li‐Shin; Kersten, Sander; Drosatos, Konstantinos; Goldberg, Ira J.

doi:10.1016/j.bbalip.2014.09.012

Cited by 79 publications

(69 citation statements)

References 61 publications

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“…Interestingly, autophagy was reduced by HFD or PPAR/ suppression, but increased by the PPAR/ agonist in murine hearts, suggesting that PPAR/-induced autophagy is beneficial toward SFA-mediated ER stress and lipotoxicity. Palmitate also induced ER stress-mediated lipotoxicity in cardiomyocytes by inhibiting sequestration of fatty acids as a less harmful form of TG in lipid droplets (129). When neutral lipid storage was induced by PPAR or acyl-CoA synthetase in human cardiomyocytes, expression levels of ER stress marker genes were significantly reduced upon palmitate treatment.…”

Section: Heartmentioning

confidence: 87%

The role of ER stress in lipid metabolism and lipotoxicity

Han

Kaufman

2016

Journal of Lipid Research

482

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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Section: Heartmentioning

confidence: 87%

The role of ER stress in lipid metabolism and lipotoxicity

Han

Kaufman

2016

Journal of Lipid Research

482

372

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“…70,71 Hence, adipocytes may be protected from palmitate-induced ER stress because of their greatly increased ability to dispose of excess palmitate in their triacylglycerol pool. 72 The expansion of the triacylglycerol pool will also increase the storage capacity of adipocytes for cholesterol 73,74 and thus may explain why cholesterol does not induce ER stress in adipocytes. Increased cholesterol 112,113 and assuming equal variabilities of the differences was used to compare the palmitate-treated samples to the untreated sample.…”

Section: Discussionmentioning

confidence: 99%

Glucose starvation and hypoxia, but not the saturated fatty acid palmitic acid or cholesterol, activate the unfolded protein response in 3T3-F442A and 3T3-L1 adipocytes

Mihai

Schröder

2015

Adipocyte

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Obesity is associated with endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) in adipose tissue. In this study we identify physiological triggers of ER stress and of the UPR in adipocytes in vitro. We show that two markers of adipose tissue remodelling in obesity, glucose starvation and hypoxia, cause ER stress in 3T3-F442A and 3T3-L1 adipocytes. Both conditions induced molecular markers of the IRE1a and PERK branches of the UPR, such as splicing of XBP1 mRNA and CHOP, as well as transcription of the ER stress responsive gene BiP. Hypoxia also induced an increase in phosphorylation of the PERK substrate eIF2a. By contrast, physiological triggers of ER stress in many other cell types, such as the saturated fatty acid palmitic acid, cholesterol, or several inflammatory cytokines including TNF-a, IL-1b, and IL-6, do not cause ER stress in 3T3-F442A and 3T3-L1 adipocytes. Our data suggest that physiological changes associated with remodelling of adipose tissue in obesity, such as hypoxia and glucose starvation, are more likely physiological ER stressors of adipocytes than the lipid overload or hyperinsulinemia associated with obesity.

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“…Knockout of adipocyte triglyceride lipase (ATGL) in mice (see review by Zechner and Kratky) increases hepatic triglyceride storage in LDs and protects against tunicamycin-induced ER stress, decreasing stress markers such as GRP78 and spliced XBP1 [98]. Similarly, in human cardiomyocyte-derived cells, palmitate-induced ER stress can be inhibited by increasing triglycerides via the overexpression of PPARγ or Acyl-CoA synthetase 1 [99]. Conversely, ER stress markers can be increased by boosting the release of free FAs from LD triglycerides via the overexpression of ATGL [99].…”

Section: 2 Roles For Lipid Droplets In Managing Cell Stressmentioning

confidence: 99%

Lipid droplet functions beyond energy storage

Welte

Gould

2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

442

358

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Lipid droplets are cytoplasmic organelles that store neutral lipids and are critically important for energy metabolism. Their function in energy storage is firmly established and increasingly well characterized. However, emerging evidence indicates that lipid droplets also play important and diverse roles in the cellular handling of lipids and proteins that may not be directly related to energy homeostasis. Lipid handling roles of droplets include the storage of hydrophobic vitamin and signaling precursors, and the management of endoplasmic reticulum and oxidative stress. Roles of lipid droplets in protein handling encompass functions in the maturation, storage, and turnover of cellular and viral polypeptides. Other potential roles of lipid droplets may be connected with their intracellular motility and, in some cases, their nuclear localization. This diversity highlights that lipid droplets are very adaptable organelles, performing different functions in different biological contexts.

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Sequestration of fatty acids in triglycerides prevents endoplasmic reticulum stress in an in vitro model of cardiomyocyte lipotoxicity

Cited by 79 publications

References 61 publications

The role of ER stress in lipid metabolism and lipotoxicity

The role of ER stress in lipid metabolism and lipotoxicity

Glucose starvation and hypoxia, but not the saturated fatty acid palmitic acid or cholesterol, activate the unfolded protein response in 3T3-F442A and 3T3-L1 adipocytes

Lipid droplet functions beyond energy storage

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