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

Colin S Mccoin,Michael L Blackburn,Melanie B Gillingham,Kikumi D Ono‐Moore,Jerry Vockley,Trina A Knotts,Jennifer E Norman,Sean H Adams

doi:10.14814/phy2.14037

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; for example, in cardiac ischemia, increased LCACs may contribute to tissue cell stress and infarct damage. Perturbed LCFA β‐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 (~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 γ, 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, β‐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.

Highlights

Alterations in blood and tissue long-chain acylcarnitines (LCACs, ≥C14 chain lengths) can occur through a number of physiological and pathophysiological metabolic events in which pools of acyl-Coenzyme A fatty acid metabolites are converted to acylcarnitines through the actions of mitochondrial carnitine palmitoyltransferase 1 (CPT 1) and CPT 2
Both the quantity and pattern of LCACs are significantly altered in persons with inherited mitochondrial long-chain fatty acid oxidation disorders (FAODs), the most common of which are CPT 2, very long chain acyl-CoA dehydrogenase (VLCAD), and longchain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiencies
Age, sex, and BMImatched long-chain FAOD and control subjects were recruited to Oregon Health & Science University (OHSU) for a study approved by the OHSU Institutional Review Board (IRB no. 817)

Summary

Introduction

Alterations in blood and tissue long-chain acylcarnitines (LCACs, ≥C14 chain lengths) can occur through a number of physiological and pathophysiological metabolic events in which pools of acyl-Coenzyme A fatty acid metabolites are converted to acylcarnitines through the actions of mitochondrial carnitine palmitoyltransferase 1 (CPT 1) and CPT 2. A mismatch between LCFA availability and complete b-oxidation is inherent to exercise, during which LCFA metabolic flux is increased and blood concentrations of acylcarnitines reflective of incomplete FAO track muscle work (Lehmann et al 2010; Zhang et al 2017). Cardiac ischemia is another condition in which tissue LCACs and other lipids accumulate markedly, especially in heart regions with ischemic damage (Idell-Wenger et al 1978; Genuth and Hoppel 1981; Vogel-van et al 2011; Liepinsh et al 2016). Myocellular concentrations of LCACs as estimated from wet weight vary widely in these dysmetabolic states, but range from >~50 lmol/L (rodent insulin-resistant muscle or LCFA-treated cultured myocytes, Emerson et al 2017; Koves et al 2008), to >~1 mmol/L (rat or rabbit cardiac ischemia; i.e., Genuth and Hoppel 1981; Idell-Wenger et al 1978; Liepinsh et al 2016)

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