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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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High inducibility of SCD1 is associated with a low inflammatory and ER stress response to palmitate in human myotubes. Myotube donors were divided by the mean of SCD1 induction by palmitate into a group with low (□) and high (▩) inducibility of SCD1. Induction of inflammatory cytokines IL-6, IL-8, and CXCL3/MIP-1β by palmitate was compared between the low and high SCD1 group. The high SCD1 group had significantly lower induction of inflammatory cytokines IL-6 (15.7- vs. 8.9-fold, P = 0.01) (A), IL-8 (15.0- vs. 9.9-fold, P = 0.03) (B), and CXCL3 (20.0- vs. 11.4-fold, P = 0.003) (C). The induction of key ER stress markers by palmitate was also compared between the low and high SCD1 group. The high SCD1 group had significantly lower induction of CHOP (5.53- vs. 3.99-fold, P = 0.04) (D) and ATF3 (6.02- vs. 4.05-fold, P = 0.02) (E) and tended to lower induction of XBP1 (1.86- vs. 1.52-fold, P = 0.13) (F).
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Figure 4: High inducibility of SCD1 is associated with a low inflammatory and ER stress response to palmitate in human myotubes. Myotube donors were divided by the mean of SCD1 induction by palmitate into a group with low (□) and high (▩) inducibility of SCD1. Induction of inflammatory cytokines IL-6, IL-8, and CXCL3/MIP-1β by palmitate was compared between the low and high SCD1 group. The high SCD1 group had significantly lower induction of inflammatory cytokines IL-6 (15.7- vs. 8.9-fold, P = 0.01) (A), IL-8 (15.0- vs. 9.9-fold, P = 0.03) (B), and CXCL3 (20.0- vs. 11.4-fold, P = 0.003) (C). The induction of key ER stress markers by palmitate was also compared between the low and high SCD1 group. The high SCD1 group had significantly lower induction of CHOP (5.53- vs. 3.99-fold, P = 0.04) (D) and ATF3 (6.02- vs. 4.05-fold, P = 0.02) (E) and tended to lower induction of XBP1 (1.86- vs. 1.52-fold, P = 0.13) (F).

Mentions: Exposure to palmitate caused a strong induction of inflammatory cytokines IL-6 (13-fold), IL-8 (12-fold), and CXCL3/macrophage inflammatory protein (MIP)-1β (17-fold) mRNA expression in human myotubes of all donors. The induction of all three inflammatory cytokines upon palmitate exposure was significantly lower in the high SCD1 group compared with the low SCD1 group (Fig. 4A–C). This further indicates that high individual inducibility of SCD1 reduces the cellular inflammatory response to palmitate.


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)

High inducibility of SCD1 is associated with a low inflammatory and ER stress response to palmitate in human myotubes. Myotube donors were divided by the mean of SCD1 induction by palmitate into a group with low (□) and high (▩) inducibility of SCD1. Induction of inflammatory cytokines IL-6, IL-8, and CXCL3/MIP-1β by palmitate was compared between the low and high SCD1 group. The high SCD1 group had significantly lower induction of inflammatory cytokines IL-6 (15.7- vs. 8.9-fold, P = 0.01) (A), IL-8 (15.0- vs. 9.9-fold, P = 0.03) (B), and CXCL3 (20.0- vs. 11.4-fold, P = 0.003) (C). The induction of key ER stress markers by palmitate was also compared between the low and high SCD1 group. The high SCD1 group had significantly lower induction of CHOP (5.53- vs. 3.99-fold, P = 0.04) (D) and ATF3 (6.02- vs. 4.05-fold, P = 0.02) (E) and tended to lower induction of XBP1 (1.86- vs. 1.52-fold, P = 0.13) (F).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Figure 4: High inducibility of SCD1 is associated with a low inflammatory and ER stress response to palmitate in human myotubes. Myotube donors were divided by the mean of SCD1 induction by palmitate into a group with low (□) and high (▩) inducibility of SCD1. Induction of inflammatory cytokines IL-6, IL-8, and CXCL3/MIP-1β by palmitate was compared between the low and high SCD1 group. The high SCD1 group had significantly lower induction of inflammatory cytokines IL-6 (15.7- vs. 8.9-fold, P = 0.01) (A), IL-8 (15.0- vs. 9.9-fold, P = 0.03) (B), and CXCL3 (20.0- vs. 11.4-fold, P = 0.003) (C). The induction of key ER stress markers by palmitate was also compared between the low and high SCD1 group. The high SCD1 group had significantly lower induction of CHOP (5.53- vs. 3.99-fold, P = 0.04) (D) and ATF3 (6.02- vs. 4.05-fold, P = 0.02) (E) and tended to lower induction of XBP1 (1.86- vs. 1.52-fold, P = 0.13) (F).
Mentions: Exposure to palmitate caused a strong induction of inflammatory cytokines IL-6 (13-fold), IL-8 (12-fold), and CXCL3/macrophage inflammatory protein (MIP)-1β (17-fold) mRNA expression in human myotubes of all donors. The induction of all three inflammatory cytokines upon palmitate exposure was significantly lower in the high SCD1 group compared with the low SCD1 group (Fig. 4A–C). This further indicates that high individual inducibility of SCD1 reduces the cellular inflammatory response to palmitate.

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