Journal
PHYSIOLOGICAL REPORTS
Volume 7, Issue 6, Pages -Publisher
WILEY
DOI: 10.14814/phy2.14037
Keywords
Carnitine; caspase-3; immunometabolism
Categories
Funding
- NIH-NIDDK [R01DK078328, R01DK07832802S1, K01DK071869]
- American Diabetes Association [1-12-BS-02]
- University of California Davis Clinical and Translational Science Center (CTSC) Pilot Award - NIH National Center for Advancing Translational Sciences [UL1TR000002]
- NIH T32 predoctoral training award - National Center for Advancing Translational Sciences, National Institutes of Health [UL1 TR000002, TL1 TR000133]
- USDA-ARS Project [6026-51000-010-05S]
- [R01-DK78755]
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Excessive cellular accumulation or exposure to lipids such as long-chain acylcarnitines (LCACs), ceramides, and others is implicated in cell stress and inflammation. Such a situation might manifest when there is a significant mismatch between long-chain fatty acid (LCFA) availability versus storage and oxidative utilization; for example, in cardiac ischemia, increased LCACs may contribute to tissue cell stress and infarct damage. Perturbed LCFA beta-oxidation is also seen in fatty acid oxidation disorders (FAODs). FAODs typically manifest with fasting- or stress-induced symptoms, and patients can manage many symptoms through control of diet and physical activity. However, episodic clinical events involving cardiac and skeletal muscle myopathies are common and can present without an obvious molecular trigger. We have speculated that systemic or tissue-specific lipotoxicity and activation of inflammation pathways contribute to long-chain FAOD pathophysiology. With this in mind, we characterized inflammatory phenotype (14 blood plasma cytokines) in resting, overnight-fasted (similar to 10 h), or exercise-challenged subjects with clinically well-controlled long-chain FAODs (n = 12; 10 long-chain 3-hydroxyacyl-CoA dehydrogenase [LCHAD]; 2 carnitine palmitoyltransferase 2 [CPT2]) compared to healthy controls (n = 12). Across experimental conditions, concentrations of three cytokines were modestly but significantly increased in FAOD (IFN gamma, IL-8, and MDC), and plasma levels of IL-10 (considered an inflammation-dampening cytokine) were significantly decreased. These novel results indicate that while asymptomatic FAOD patients do not display gross body-wide inflammation even after moderate exercise, beta-oxidation deficiencies might be associated with chronic and subtle activation of sterile inflammation. Further studies are warranted to determine if inflammation is more apparent in poorly controlled long-chain FAOD or when long-chain FAOD-associated symptoms are present.
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