Decrease in Membrane Phospholipid Unsaturation Induces Unfolded Protein Response

Ariyama, Hiroyuki; Kono, Nozomu; Matsuda, Shinji; Inoué, Takao; Arai, Hiroyuki

doi:10.1074/jbc.m110.126870

Cited by 248 publications

(232 citation statements)

References 51 publications

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“…PERK is also activated by membrane lipid saturation (10,19). To test if luminal-independent signals are involved in that process too, an ER-targeted PERK lacking its luminal stresssensing domain (ΔLD-PERK, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Increased membrane lipid saturation by genetic or pharmacological inhibition of stearoyl CoA desaturase 1 (SCD1) (19) and by loading of cultured cells with the saturated fatty acid palmitate (10) has been reported to promote UPR signaling. In keeping with these observations, exposure to an SCD1 inhibitor resulted in a fourfold increase in Xbp1 mRNA splicing in FL-IRE1α-expressing cells, which increased to eightfold when compounded with palmitate loading.…”

Section: Resultsmentioning

confidence: 99%

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Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains

Volmer

Ploeg

Ron

2013

Proc. Natl. Acad. Sci. U.S.A.

574

568

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Endoplasmic reticulum (ER) stress sensors use a related luminal domain to monitor the unfolded protein load and convey the signal to downstream effectors, signaling an unfolded protein response (UPR) that maintains compartment-specific protein folding homeostasis. Surprisingly, perturbation of cellular lipid composition also activates the UPR, with important consequences in obesity and diabetes. However, it is unclear if direct sensing of the lipid perturbation contributes to UPR activation. We found that mutant mammalian ER stress sensors, IRE1α and PERK, lacking their luminal unfolded protein stress-sensing domain, nonetheless retained responsiveness to increased lipid saturation. Lipid saturationmediated activation in cells required an ER-spanning transmembrane domain and was positively regulated in vitro by acyl-chain saturation in reconstituted liposomes. These observations suggest that direct sensing of the lipid composition of the ER membrane contributes to the UPR.lipid bilayer | membrane fluidity | integral membrane protein | palmitic acid P rotein folding homeostasis in the lumen of the endoplasmic reticulum (ER) requires matching the flux of unfolded proteins entering the organelle to the capacity of the machinery for processing this biosynthetic load. To achieve this, eukaryotes have evolved signaling pathways that couple ER perturbation (or stress) to a rectifying gene expression program referred to as the unfolded protein response (UPR). Upstream in these pathways are ER localized transmembrane proteins, such as the product of the Inositol REquiring 1 gene (IRE1) (1, 2) and Protein kinase r-like Endoplasmic Reticulum Kinase (PERK) (3), that sense a luminal stress signal(s) and convey it to downstream effectors via their enzymatic activities.The unfolded protein load in the ER regulates IRE1 and PERK activation by two complementary processes: One involves the luminal chaperone immunoglobulin heavy chain binding protein (BiP), which complexes with the luminal domain of IRE1 and PERK, maintaining the enzymes in an inactive, monomeric form. Increases in unfolded protein correlate with disruption of this repressive complex, oligomerization, and activation of the sensor (4-6). The other process involves unfolded proteins that may also engage the stress-sensing luminal domain directly and favor its dimerization and thereby downstream signaling (7,8).Perturbation of cellular lipid composition also activates the UPR. Enhanced UPR signaling has been observed in cholesterol-loaded macrophages (9), in pancreatic beta cells exposed to saturated fatty acids (10), and in the liver of mice fed a high-fat diet (11) and is believed to play a role in the lipotoxicity associated with obesity and type II diabetes mellitus. In yeast, too, lipid perturbation activates the UPR (12, 13), but the mechanisms remain obscure.In mammals, altered membrane lipid composition leads to ER calcium depletion (11,14). This is proposed to promote unfolded protein stress by interfering with calcium-dependent chaperones and enzymes requir...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains

Volmer

Ploeg

Ron

2013

Proc. Natl. Acad. Sci. U.S.A.

574

568

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“…It has been demonstrated that insufficient desaturase activity (SCD1 knockdown) or decreased incorporation of unsaturated fatty acids in membrane phospholipids (LPCAT3 knockdown) can synergistically induce the UPR. The effect is likely due to a decrease in membrane phospholipids unsaturation as it is further enhanced by saturated while it is rescued by unsaturated fatty acids [69] ( Figure 2B). Recent findings suggest that ER lipid perturbation can trigger the UPR directly and independently of luminal accumulation of unfolded proteins.…”

Section: Lipotoxic Er Stressmentioning

confidence: 99%

Lipotoxicity in the liver

Zámbó

Simon-Szabó

Szelényi

et al. 2013

WJH

164

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Obesity due to excessive food intake and the lack of physical activity is becoming one of the most serious public health problems of the 21 st century. With the increasing prevalence of obesity, non-alcoholic fatty liver disease is also emerging as a pandemic. While previously this pathophysiological condition was mainly attributed to triglyceride accumulation in hepatocytes, recent data show that the development of oxidative stress, lipid peroxidation, cell death, inflammation and fibrosis are mostly due to accumulation of fatty acids, and the altered composition of membrane phospholipids. In fact, triglyceride accumulation might play a protective role, and the higher toxicity of saturated or trans fatty acids seems to be the consequence of a blockade in triglyceride synthesis. Increased membrane saturation can profoundly disturb cellular homeostasis by impairing the function of membrane receptors, channels and transporters. However, it also induces endoplasmic reticulum stress via novel sensing mechanisms of the organelle's stress receptors. The triggered signaling pathways in turn largely contribute to the development of insulin resistance and apoptosis. These findings have substantiated the lipotoxic liver injury hypothesis for the pathomechanism of hepatosteatosis. This minireview focuses on the metabolic and redox aspects of lipotoxicity and lipoapoptosis, with special regards on the involvement of endoplasmic reticulum stress responses. Key words: Saturated fatty acid; Lipotoxicity; Steatosis; Lipoapoptosis; Endoplasmic reticulum stress Core tip: Surplus of free fatty acids contributes to hepatic injuries in obesity and type 2 diabetes. Intracellular accumulation of fatty acyl-CoA causes oxidative and endoplasmic reticulum (ER) stress, which lead to cell death, inflammation and fibrosis. Steatohepatosis is the consequence of an intensive fat synthesis, aiming to reduce the metabolic burden. The higher toxicity of saturated vs unsaturated fatty acids is partly due to a limited capacity of the liver cells to insert them into triglycerides. Moreover, increased membrane saturation triggers the ER stress response though a unique mechanism, which aggravates the metabolic derangements and liver injuries.

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“…calcium storage and membrane lipid composition. [4][5][6][7][8][9][10][11] For example, decreased synthesis of phosphatidylcholine (PC), altered fatty acid desaturation, abnormal sterol levels, and organismal obesity all induce the UPR ER . …”

Section: Introductionmentioning

confidence: 99%

Membrane lipids and the endoplasmic reticulum unfolded protein response: An interesting relationship

Hou

Taubert

2014

Worm

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Decrease in Membrane Phospholipid Unsaturation Induces Unfolded Protein Response

Cited by 248 publications

References 51 publications

Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains

Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains

Lipotoxicity in the liver

Membrane lipids and the endoplasmic reticulum unfolded protein response: An interesting relationship

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