Inhibition of macrophage fatty acid β-oxidation exacerbates palmitate-induced inflammatory and endoplasmic reticulum stress responses

Aims/hypothesis Saturated fatty acids (SFAs) such as palmitate activate inflammatory pathways and elicit an endoplasmic reticulum (ER) stress response in macrophages, thereby contributing to the development of insulin resistance linked to the metabolic syndrome. This study addressed the question of...

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Bibliographic Details
Published in:Diabetologia 2014-05, Vol.57 (5), p.1067-1077
Main Authors: Namgaladze, Dmitry, Lips, Sebastian, Leiker, Thomas J., Murphy, Robert C., Ekroos, Kim, Ferreiros, Nerea, Geisslinger, Gerd, Brüne, Bernhard
Format: Article
Language:English
Subjects:
Biological and medical sciences
Carnitine O-Palmitoyltransferase - metabolism
Cell Line, Tumor
Diabetes. Impaired glucose tolerance
Diglycerides - metabolism
Endocrine pancreas. Apud cells (diseases)
Endocrinopathies
Endoplasmic Reticulum - metabolism
Endoplasmic Reticulum Stress
Etiopathogenesis. Screening. Investigations. Target tissue resistance
Fatty Acids - metabolism
Human Physiology
Humans
Inflammation
Insulin Resistance
Internal Medicine
Macrophages - metabolism
Medical sciences
Medicine
Medicine & Public Health
Membrane Microdomains
Metabolic Diseases
Metabolic Syndrome - metabolism
Mitochondria - metabolism
Oxygen - metabolism
Palmitates - metabolism
Triglycerides - metabolism
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Summary:Aims/hypothesis Saturated fatty acids (SFAs) such as palmitate activate inflammatory pathways and elicit an endoplasmic reticulum (ER) stress response in macrophages, thereby contributing to the development of insulin resistance linked to the metabolic syndrome. This study addressed the question of whether or not mitochondrial fatty acid β-oxidation (FAO) affects macrophage responses to SFA. Methods We modulated the activity of carnitine palmitoyl transferase 1A (CPT1A) in macrophage-differentiated THP-1 monocytic cells using genetic or pharmacological approaches, treated the cells with palmitate and analysed the proinflammatory and ER stress signatures. Results To inhibit FAO, we created THP-1 cells with a stable knockdown (KD) of CPT1A and differentiated them to macrophages. Consequently, in CPT1A-silenced cells FAO was reduced. CPT1A KD in THP-1 macrophages increased proinflammatory signalling, cytokine expression and ER stress responses after palmitate treatment. In addition, in human primary macrophages CPT1A KD elevated palmitate-induced inflammatory gene expression. Pharmacological inhibition of FAO with etomoxir recapitulated the CPT1A KD phenotype. Conversely, overexpression of a malonyl-CoA-insensitive CPT1A M593S mutant reduced inflammatory and ER stress responses to palmitate in THP-1 macrophages. Macrophages with a CPT1A KD accumulated diacylglycerols and triacylglycerols after palmitate treatment, while ceramide accumulation remained unaltered. Moreover, lipidomic analysis of ER phospholipids revealed increased palmitate incorporation into phosphatidylethanolamine and phosphatidylserine classes associated with the CPT1A KD. Conclusions/interpretation Our data indicate that FAO attenuates inflammatory and ER stress responses in SFA-exposed macrophages, suggesting an anti-inflammatory impact of drugs that activate FAO.
ISSN:0012-186X
1432-0428
DOI:10.1007/s00125-014-3173-4