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Decrease in membrane phospholipid unsaturation induces unfolded protein response.

Ariyama H, Kono N, Matsuda S, Inoue T, Arai H - J. Biol. Chem. (2010)

Bottom Line: In this study we showed that stearoyl-CoA desaturase 1 (SCD1) knockdown increased the amount of saturated fatty acids and decreased that of monounsaturated fatty acids in phospholipids without affecting the amount or the composition of free fatty acid and induced unfolded protein response (UPR), evidenced by increased expression of C/EBP homologous protein (CHOP) and glucose-regulated protein 78 (GRP78) mRNAs and splicing of Xbox-binding protein 1 (XBP1) mRNA.Finally we showed that palmitic acid-induced UPR was significantly enhanced by LPCAT3 knockdown as well as SCD1 knockdown.These results suggest that a decrease in membrane phospholipid unsaturation induces UPR.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan.

ABSTRACT
Various kinds of fatty acids are distributed in membrane phospholipids in mammalian cells and tissues. The degree of fatty acid unsaturation in membrane phospholipids affects many membrane-associated functions and can be influenced by diet and by altered activities of lipid-metabolizing enzymes such as fatty acid desaturases. However, little is known about how mammalian cells respond to changes in phospholipid fatty acid composition. In this study we showed that stearoyl-CoA desaturase 1 (SCD1) knockdown increased the amount of saturated fatty acids and decreased that of monounsaturated fatty acids in phospholipids without affecting the amount or the composition of free fatty acid and induced unfolded protein response (UPR), evidenced by increased expression of C/EBP homologous protein (CHOP) and glucose-regulated protein 78 (GRP78) mRNAs and splicing of Xbox-binding protein 1 (XBP1) mRNA. SCD1 knockdown-induced UPR was rescued by various unsaturated fatty acids and was enhanced by saturated fatty acid. Lysophosphatidylcholine acyltransferase 3 (LPCAT3), which incorporates preferentially polyunsaturated fatty acids into phosphatidylcholine, was up-regulated in SCD1 knockdown cells. Knockdown of LPCAT3 synergistically enhanced UPR with SCD1 knockdown. Finally we showed that palmitic acid-induced UPR was significantly enhanced by LPCAT3 knockdown as well as SCD1 knockdown. These results suggest that a decrease in membrane phospholipid unsaturation induces UPR.

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SCD1 knockdown increases palmitic acid-induced UPR. At 48 h after siRNA transfection, cells were further incubated for 12 h in media supplemented with 16:0. The expression level of each gene was normalized to the GAPDH gene and is represented as -fold induction over untreated siControl. The data represent the mean ± S.E. of three experiments. The asterisks indicate significant differences compared with siControl-transfected cells (p < 0.01).
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Figure 5: SCD1 knockdown increases palmitic acid-induced UPR. At 48 h after siRNA transfection, cells were further incubated for 12 h in media supplemented with 16:0. The expression level of each gene was normalized to the GAPDH gene and is represented as -fold induction over untreated siControl. The data represent the mean ± S.E. of three experiments. The asterisks indicate significant differences compared with siControl-transfected cells (p < 0.01).

Mentions: We also examined the effect of exposure of 16:0 in control and SCD1 knockdown cells. To examine CHOP expression in 16:0-treated cells, we harvested cells before excessive cell death occurred. In control cells, 50 μm 16:0 exposure for 12 h did not significantly increase CHOP expression. In SCD1 knockdown cells, however, significant increase in CHOP expression was observed after exposure to 50 μm 16:0 (Fig. 5).


Decrease in membrane phospholipid unsaturation induces unfolded protein response.

Ariyama H, Kono N, Matsuda S, Inoue T, Arai H - J. Biol. Chem. (2010)

SCD1 knockdown increases palmitic acid-induced UPR. At 48 h after siRNA transfection, cells were further incubated for 12 h in media supplemented with 16:0. The expression level of each gene was normalized to the GAPDH gene and is represented as -fold induction over untreated siControl. The data represent the mean ± S.E. of three experiments. The asterisks indicate significant differences compared with siControl-transfected cells (p < 0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2903364&req=5

Figure 5: SCD1 knockdown increases palmitic acid-induced UPR. At 48 h after siRNA transfection, cells were further incubated for 12 h in media supplemented with 16:0. The expression level of each gene was normalized to the GAPDH gene and is represented as -fold induction over untreated siControl. The data represent the mean ± S.E. of three experiments. The asterisks indicate significant differences compared with siControl-transfected cells (p < 0.01).
Mentions: We also examined the effect of exposure of 16:0 in control and SCD1 knockdown cells. To examine CHOP expression in 16:0-treated cells, we harvested cells before excessive cell death occurred. In control cells, 50 μm 16:0 exposure for 12 h did not significantly increase CHOP expression. In SCD1 knockdown cells, however, significant increase in CHOP expression was observed after exposure to 50 μm 16:0 (Fig. 5).

Bottom Line: In this study we showed that stearoyl-CoA desaturase 1 (SCD1) knockdown increased the amount of saturated fatty acids and decreased that of monounsaturated fatty acids in phospholipids without affecting the amount or the composition of free fatty acid and induced unfolded protein response (UPR), evidenced by increased expression of C/EBP homologous protein (CHOP) and glucose-regulated protein 78 (GRP78) mRNAs and splicing of Xbox-binding protein 1 (XBP1) mRNA.Finally we showed that palmitic acid-induced UPR was significantly enhanced by LPCAT3 knockdown as well as SCD1 knockdown.These results suggest that a decrease in membrane phospholipid unsaturation induces UPR.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan.

ABSTRACT
Various kinds of fatty acids are distributed in membrane phospholipids in mammalian cells and tissues. The degree of fatty acid unsaturation in membrane phospholipids affects many membrane-associated functions and can be influenced by diet and by altered activities of lipid-metabolizing enzymes such as fatty acid desaturases. However, little is known about how mammalian cells respond to changes in phospholipid fatty acid composition. In this study we showed that stearoyl-CoA desaturase 1 (SCD1) knockdown increased the amount of saturated fatty acids and decreased that of monounsaturated fatty acids in phospholipids without affecting the amount or the composition of free fatty acid and induced unfolded protein response (UPR), evidenced by increased expression of C/EBP homologous protein (CHOP) and glucose-regulated protein 78 (GRP78) mRNAs and splicing of Xbox-binding protein 1 (XBP1) mRNA. SCD1 knockdown-induced UPR was rescued by various unsaturated fatty acids and was enhanced by saturated fatty acid. Lysophosphatidylcholine acyltransferase 3 (LPCAT3), which incorporates preferentially polyunsaturated fatty acids into phosphatidylcholine, was up-regulated in SCD1 knockdown cells. Knockdown of LPCAT3 synergistically enhanced UPR with SCD1 knockdown. Finally we showed that palmitic acid-induced UPR was significantly enhanced by LPCAT3 knockdown as well as SCD1 knockdown. These results suggest that a decrease in membrane phospholipid unsaturation induces UPR.

Show MeSH