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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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SCD1 mRNA expression is stimulated by the saturated fatty acid palmitate. A: Change in SCD1 mRNA expression in primary human myotubes of 39 donors is displayed after 20 h exposure to 0.5 mmol/l palmitate or the BSA control. B: Fold changes of SCD1 expression after palmitate exposure are displayed. The induction of SCD1 expression ranges from 0.46- to 4.38-fold. SCD1 mRNA expression is stimulated 1.95-fold by palmitate exposure. *P < 0.0001 (significantly different).
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Figure 1: SCD1 mRNA expression is stimulated by the saturated fatty acid palmitate. A: Change in SCD1 mRNA expression in primary human myotubes of 39 donors is displayed after 20 h exposure to 0.5 mmol/l palmitate or the BSA control. B: Fold changes of SCD1 expression after palmitate exposure are displayed. The induction of SCD1 expression ranges from 0.46- to 4.38-fold. SCD1 mRNA expression is stimulated 1.95-fold by palmitate exposure. *P < 0.0001 (significantly different).

Mentions: First, we examined the effect of palmitate exposure on SCD1 mRNA expression in primary myotubes of 39 donors. The anthropometric and metabolic characteristics of the myotube donors are displayed in Table 1. On average, we observed a doubling of SCD1 mRNA expression after palmitate exposure (0.5 mmol/l, 20 h). However, basal SCD1 mRNA expression levels, as well as the upregulation of SCD1 mRNA expression in response to palmitate, showed a remarkable interindividual variation. In myotubes of three donors, the SCD1 expression was reduced, while most others showed a strong but variable increase (0.46- to 4.38-fold) (Fig. 1A and B).


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)

SCD1 mRNA expression is stimulated by the saturated fatty acid palmitate. A: Change in SCD1 mRNA expression in primary human myotubes of 39 donors is displayed after 20 h exposure to 0.5 mmol/l palmitate or the BSA control. B: Fold changes of SCD1 expression after palmitate exposure are displayed. The induction of SCD1 expression ranges from 0.46- to 4.38-fold. SCD1 mRNA expression is stimulated 1.95-fold by palmitate exposure. *P < 0.0001 (significantly different).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2712792&req=5

Figure 1: SCD1 mRNA expression is stimulated by the saturated fatty acid palmitate. A: Change in SCD1 mRNA expression in primary human myotubes of 39 donors is displayed after 20 h exposure to 0.5 mmol/l palmitate or the BSA control. B: Fold changes of SCD1 expression after palmitate exposure are displayed. The induction of SCD1 expression ranges from 0.46- to 4.38-fold. SCD1 mRNA expression is stimulated 1.95-fold by palmitate exposure. *P < 0.0001 (significantly different).
Mentions: First, we examined the effect of palmitate exposure on SCD1 mRNA expression in primary myotubes of 39 donors. The anthropometric and metabolic characteristics of the myotube donors are displayed in Table 1. On average, we observed a doubling of SCD1 mRNA expression after palmitate exposure (0.5 mmol/l, 20 h). However, basal SCD1 mRNA expression levels, as well as the upregulation of SCD1 mRNA expression in response to palmitate, showed a remarkable interindividual variation. In myotubes of three donors, the SCD1 expression was reduced, while most others showed a strong but variable increase (0.46- to 4.38-fold) (Fig. 1A and B).

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