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.
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.


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.
Peter
Andreas
A
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
Weigert
Cora
C
Staiger
Harald
H
Machicao
Fausto
F
Schick
Fritz
F
Machann
Jürgen
J
Stefan
Norbert
N
Thamer
Claus
C
Häring
Hans-Ulrich
HU
Schleicher
Erwin
E
D001823:Body Composition; D002470:Cell Survival / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000502:physiology*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000503:physiopathology / Q000517:prevention & control*; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance / Q000502:physiology; D008055:Lipids / Q000502:physiology*; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D019308:Palmitic Acid / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013230:Stearoyl-CoA Desaturase / Q000235:genetics* / Q000378:metabolism
D005230:Fatty Acids, Nonesterified; D007328:Insulin; D008055:Lipids; D012333:RNA, Messenger; D019308:Palmitic Acid; D013230:Stearoyl-CoA Desaturase