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Individual stearoyl-coa desaturase 1 expression modulates endoplasmic reticulum stress and inflammation in human myotubes and is associated with skeletal muscle lipid storage and insulin sensitivity in vivo.

Peter A, Weigert C, Staiger H, Machicao F, Schick F, Machann J, Stefan N, Thamer C, Häring HU, Schleicher E - Diabetes (2009)

Bottom Line: Stearoyl-CoA desaturase 1 (SCD1) plays a key role in preventing lipotoxic effects, as it converts SFAs to less harmful monounsaturated fatty acids.In primary human myotubes, high SCD1 inducibility was associated with a low inflammatory (interleukin [IL]-6, IL-8, and chemokine [CXC motif] ligand 3 [CXCL3]) and ER stress (CCAAT/enhancer binding protein [C/EBP] homologous protein, activating transcription factor 3 [ATF3], and X-box binding protein 1 [XBP1]) response to palmitate exposure.This may describe individuals with increased capability of innoxious free fatty acid handling and benign triglyceride storage.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology, and Clinical Chemistry, University of Tübingen, Tübingen, Germany. andreas.peter@med.uni-tuebingen.de

ABSTRACT

Objective: Increased plasma levels of free fatty acids occur in obesity and type 2 diabetes and contribute to the development of insulin resistance. Saturated fatty acids (SFAs) such as palmitate especially have lipotoxic effects leading to endoplasmatic reticulum (ER) stress, inflammation, and insulin resistance. Stearoyl-CoA desaturase 1 (SCD1) plays a key role in preventing lipotoxic effects, as it converts SFAs to less harmful monounsaturated fatty acids. Here, we tested the hypothesis that individual differences in the regulation of SCD1 expression by palmitate exist and influence insulin sensitivity and the cellular response to palmitate.

Research design and methods: Palmitate-induced gene expression was studied in primary human myotubes of 39 metabolically characterized individuals, as well as in an SCD1-overexpressing cell culture model.

Results: SCD1 mRNA expression and inducibility by palmitate in cultured myotubes showed a broad interindividual variation, presumably due to inheritable characteristics of the donors. Overexpression of SCD1 prevented the inflammatory and ER stress response to palmitate exposure. In primary human myotubes, high SCD1 inducibility was associated with a low inflammatory (interleukin [IL]-6, IL-8, and chemokine [CXC motif] ligand 3 [CXCL3]) and ER stress (CCAAT/enhancer binding protein [C/EBP] homologous protein, activating transcription factor 3 [ATF3], and X-box binding protein 1 [XBP1]) response to palmitate exposure. Finally, palmitate-stimulated SCD1 mRNA expression, positively correlated with intramyocellular lipid (IMCL) content of the donors, was measured by (1)H-magnetic resonance spectroscopy. After adjustment for IMCL, SCD1 expression and inducibility were positively correlated with insulin sensitivity.

Conclusions: We hypothesize that myocellular SCD1 inducibility by palmitate is an individual characteristic that modulates lipid storage, palmitate-induced inflammation, ER stress, and insulin resistance. This may describe individuals with increased capability of innoxious free fatty acid handling and benign triglyceride storage.

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Overexpression of SCD1 prevents palmitate-induced inflammatory cytokine induction and ER stress. The expression of inflammatory cytokines (A and B) and ER stress response markers (C–F) in response to palmitate or oleate (0.5 mmol/l; 20 h). Exposure in SCD1 cells and control cells is displayed. Palmitate, but not oleate, induces the expression of inflammatory cytokines. Overexpression of SCD1 almost completely prevents the induction of IL-8 and CXCL3 by palmitate. The ER stress response markers ATF3, CHOP, XBP1, and the spliced form XBP1s are increased by palmitate, but not oleate, exposure. Overexpression of SCD1 almost completely prevents the induction of ATF3, CHOP, XBP1, and the spliced form XBP1s by palmitate. Means ± SE of n = 6 are displayed. *Significantly different palmitate vs. BSA exposure, P < 0.05; **P < 0.001; #Significantly different SCD1 vs. control cells, P < 0.001. □, control; ▩, SCD1.
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Figure 3: Overexpression of SCD1 prevents palmitate-induced inflammatory cytokine induction and ER stress. The expression of inflammatory cytokines (A and B) and ER stress response markers (C–F) in response to palmitate or oleate (0.5 mmol/l; 20 h). Exposure in SCD1 cells and control cells is displayed. Palmitate, but not oleate, induces the expression of inflammatory cytokines. Overexpression of SCD1 almost completely prevents the induction of IL-8 and CXCL3 by palmitate. The ER stress response markers ATF3, CHOP, XBP1, and the spliced form XBP1s are increased by palmitate, but not oleate, exposure. Overexpression of SCD1 almost completely prevents the induction of ATF3, CHOP, XBP1, and the spliced form XBP1s by palmitate. Means ± SE of n = 6 are displayed. *Significantly different palmitate vs. BSA exposure, P < 0.05; **P < 0.001; #Significantly different SCD1 vs. control cells, P < 0.001. □, control; ▩, SCD1.

Mentions: After having characterized the SCD1 cell line, we determined the induction of inflammatory cytokines and key ER stress markers upon palmitate and oleate exposure (0.5 mmol/l, 20 h). Palmitate strongly induced the mRNA expression of the inflammatory cytokines IL-8 (17-fold) and CXCL3 (3.6-fold) in control cells but not in SCD1-overexpressing cells (Fig. 3A and B). Oleate, a MUFA and a product of SCD1 action, did not induce these inflammatory cytokines. IL-6 mRNA was below detection limits in these cells by RT-PCR. Next, we investigated palmitate-induced ER stress, which is a potential molecular link between obesity, elevated FFAs, insulin resistance, and the progression to diabetes (1). The ER stress markers CHOP, ATF3, XBP1, and the spliced form XBP1s were also significantly induced after palmitate exposure (Fig. 3C–F). In contrast, oleate did not induce expression of the ER stress markers. The induction of inflammatory and ER stress markers IL-8, CXCL3, ATF3, XBP1, and XBP1s was almost completely prevented in SCD1-overexpressing cells (Fig. 3A–F). These experiments demonstrate that SCD1 overexpression can prevent palmitate-induced inflammatory response, ER stress, and lipotoxicity.


Individual stearoyl-coa desaturase 1 expression modulates endoplasmic reticulum stress and inflammation in human myotubes and is associated with skeletal muscle lipid storage and insulin sensitivity in vivo.

Peter A, Weigert C, Staiger H, Machicao F, Schick F, Machann J, Stefan N, Thamer C, Häring HU, Schleicher E - Diabetes (2009)

Overexpression of SCD1 prevents palmitate-induced inflammatory cytokine induction and ER stress. The expression of inflammatory cytokines (A and B) and ER stress response markers (C–F) in response to palmitate or oleate (0.5 mmol/l; 20 h). Exposure in SCD1 cells and control cells is displayed. Palmitate, but not oleate, induces the expression of inflammatory cytokines. Overexpression of SCD1 almost completely prevents the induction of IL-8 and CXCL3 by palmitate. The ER stress response markers ATF3, CHOP, XBP1, and the spliced form XBP1s are increased by palmitate, but not oleate, exposure. Overexpression of SCD1 almost completely prevents the induction of ATF3, CHOP, XBP1, and the spliced form XBP1s by palmitate. Means ± SE of n = 6 are displayed. *Significantly different palmitate vs. BSA exposure, P < 0.05; **P < 0.001; #Significantly different SCD1 vs. control cells, P < 0.001. □, control; ▩, SCD1.
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Figure 3: Overexpression of SCD1 prevents palmitate-induced inflammatory cytokine induction and ER stress. The expression of inflammatory cytokines (A and B) and ER stress response markers (C–F) in response to palmitate or oleate (0.5 mmol/l; 20 h). Exposure in SCD1 cells and control cells is displayed. Palmitate, but not oleate, induces the expression of inflammatory cytokines. Overexpression of SCD1 almost completely prevents the induction of IL-8 and CXCL3 by palmitate. The ER stress response markers ATF3, CHOP, XBP1, and the spliced form XBP1s are increased by palmitate, but not oleate, exposure. Overexpression of SCD1 almost completely prevents the induction of ATF3, CHOP, XBP1, and the spliced form XBP1s by palmitate. Means ± SE of n = 6 are displayed. *Significantly different palmitate vs. BSA exposure, P < 0.05; **P < 0.001; #Significantly different SCD1 vs. control cells, P < 0.001. □, control; ▩, SCD1.
Mentions: After having characterized the SCD1 cell line, we determined the induction of inflammatory cytokines and key ER stress markers upon palmitate and oleate exposure (0.5 mmol/l, 20 h). Palmitate strongly induced the mRNA expression of the inflammatory cytokines IL-8 (17-fold) and CXCL3 (3.6-fold) in control cells but not in SCD1-overexpressing cells (Fig. 3A and B). Oleate, a MUFA and a product of SCD1 action, did not induce these inflammatory cytokines. IL-6 mRNA was below detection limits in these cells by RT-PCR. Next, we investigated palmitate-induced ER stress, which is a potential molecular link between obesity, elevated FFAs, insulin resistance, and the progression to diabetes (1). The ER stress markers CHOP, ATF3, XBP1, and the spliced form XBP1s were also significantly induced after palmitate exposure (Fig. 3C–F). In contrast, oleate did not induce expression of the ER stress markers. The induction of inflammatory and ER stress markers IL-8, CXCL3, ATF3, XBP1, and XBP1s was almost completely prevented in SCD1-overexpressing cells (Fig. 3A–F). These experiments demonstrate that SCD1 overexpression can prevent palmitate-induced inflammatory response, ER stress, and lipotoxicity.

Bottom Line: Stearoyl-CoA desaturase 1 (SCD1) plays a key role in preventing lipotoxic effects, as it converts SFAs to less harmful monounsaturated fatty acids.In primary human myotubes, high SCD1 inducibility was associated with a low inflammatory (interleukin [IL]-6, IL-8, and chemokine [CXC motif] ligand 3 [CXCL3]) and ER stress (CCAAT/enhancer binding protein [C/EBP] homologous protein, activating transcription factor 3 [ATF3], and X-box binding protein 1 [XBP1]) response to palmitate exposure.This may describe individuals with increased capability of innoxious free fatty acid handling and benign triglyceride storage.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology, and Clinical Chemistry, University of Tübingen, Tübingen, Germany. andreas.peter@med.uni-tuebingen.de

ABSTRACT

Objective: Increased plasma levels of free fatty acids occur in obesity and type 2 diabetes and contribute to the development of insulin resistance. Saturated fatty acids (SFAs) such as palmitate especially have lipotoxic effects leading to endoplasmatic reticulum (ER) stress, inflammation, and insulin resistance. Stearoyl-CoA desaturase 1 (SCD1) plays a key role in preventing lipotoxic effects, as it converts SFAs to less harmful monounsaturated fatty acids. Here, we tested the hypothesis that individual differences in the regulation of SCD1 expression by palmitate exist and influence insulin sensitivity and the cellular response to palmitate.

Research design and methods: Palmitate-induced gene expression was studied in primary human myotubes of 39 metabolically characterized individuals, as well as in an SCD1-overexpressing cell culture model.

Results: SCD1 mRNA expression and inducibility by palmitate in cultured myotubes showed a broad interindividual variation, presumably due to inheritable characteristics of the donors. Overexpression of SCD1 prevented the inflammatory and ER stress response to palmitate exposure. In primary human myotubes, high SCD1 inducibility was associated with a low inflammatory (interleukin [IL]-6, IL-8, and chemokine [CXC motif] ligand 3 [CXCL3]) and ER stress (CCAAT/enhancer binding protein [C/EBP] homologous protein, activating transcription factor 3 [ATF3], and X-box binding protein 1 [XBP1]) response to palmitate exposure. Finally, palmitate-stimulated SCD1 mRNA expression, positively correlated with intramyocellular lipid (IMCL) content of the donors, was measured by (1)H-magnetic resonance spectroscopy. After adjustment for IMCL, SCD1 expression and inducibility were positively correlated with insulin sensitivity.

Conclusions: We hypothesize that myocellular SCD1 inducibility by palmitate is an individual characteristic that modulates lipid storage, palmitate-induced inflammation, ER stress, and insulin resistance. This may describe individuals with increased capability of innoxious free fatty acid handling and benign triglyceride storage.

Show MeSH
Related in: MedlinePlus