Blood cytokine patterns suggest a modest inflammation phenotype in subjects with long-chain fatty acid acid oxidation disorders

Authors: MCCOIN, COLIN - University Of Kansas Medical School; GILLINGHAM, MELANIE - Oregon Health & Science University; KNOTTS, TRINA - University Of California, Davis; VOCKLEY, JERRY - University Of Pittsburgh; ONO-MOORE, KIKUMI - Arkansas Children'S Nutrition Research Center (ACNC); BLACKBURN, MICHAEL - Arkansas Children'S Nutrition Research Center (ACNC); NORMAN, JENNIFER - University Of California, Davis; Ferruzzi, Mario

Submitted to: Physiological Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/5/2019
Publication Date: 3/25/2019
Citation: McCoin, C.S., Gillingham, M.B., Knotts, T.A., Vockley, J., Ono-Moore, K.D., Blackburn, M.L., Norman, J.E., Adams, S.H. 2019. Blood cytokine patterns suggest a modest inflammation phenotype in subjects with long-chain fatty acid acid oxidation disorders. Physiological Reports. https://doi.org/10.14814/phy2.14037.
DOI: https://doi.org/10.14814/phy2.14037

Interpretive Summary: One proposal for the chronic inflammation associated with obesity is excessive tissue accumulation or exposure to fats (lipids) such as long-chain acylcarnitines (LCACs), ceramides, and others that are implicated in cell stress pathways. Lipids may also be involved in "post-meal inflammation" that has been reported under conditions of high dietary fat intake. Despite these assertions, evidence for fat-induced inflammation in humans remains mixed, and further research is needed to understand how lipid metabolism relates to immune activation and tissue stress outcomes. Some unique models and situations in which fat metabolism is disrupted allow study of this question in detail. For instance, in cardiac ischemia (heart pathology associated with acute loss of oxygen to the tissue), increased LCACs and other lipids is evident and correlate with tissue cell stress and infarct damage. Perturbed fat oxidation is also seen in rare cases of persons born with fatty acid oxidation disorders (FAODs). FAODs typically manifest with fasting- or stress-induced symptoms, which can be largely avoided through careful control of diet and physical activity. However, episodic clinical events involving cardiac and skeletal muscle myopathies are common and can present without an obvious trigger. We have speculated that systemic or tissue-specific lipotoxicity and activation of inflammation pathways contribute to FAOD pathophysiology. Thus, the FAOD situation provides a unique opportunity to learn more about normal and abnormal fat-inflammation connections. With this in mind, we characterized inflammatory phenotype (14 blood plasma cytokines) in resting, overnight-fasted (~10 h), or exercise-challenged subjects with clinically well-controlled 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 3 "pro-inflammatory" cytokines were modestly but significantly increased in FAOD (IFN', 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, a mismatch between fat availability in tissues with the level of fat combustion to energy may be associated with chronic activation of "sterile inflammation" (inflammation absent of pathogens, caused by altered metabolic signals from the body). These results support the idea that disrupted fat metabolism impacts a person's inflammatory status. Thus, changing dietary patterns and physical fitness to optimize the efficiency of tissue fat metabolism has potential to improve health by thwarting chronic inflammation.

Technical Abstract: 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; e.g., in cardiac ischemia, increased LCACs may contribute to tissue cell stress and infarct damage. Perturbed LCFA B-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 trigger. We have speculated that systemic or tissue-specific lipotoxicity and activation of inflammation pathways contribute to FAOD pathophysiology. With this in mind, we characterized inflammatory phenotype (14 blood plasma cytokines) in resting, overnight-fasted (~10 h), or exercise-challenged subjects with clinically well-controlled 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 3 cytokines were modestly but significantly increased in FAOD (IFNy, 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, B-oxidation deficiencies may be associated with chronic activation of “sterile inflammation.” Further studies are warranted to determine if inflammation is more apparent in poorly-controlled FAOD or when FAOD-associated symptoms are present.