Acylcarnitines activate proinflammatory signaling pathways

Abstract

Incomplete β-oxidation of fatty acids in mitochondria is a feature of insulin resistance and type 2 diabetes mellitus (T2DM). Previous studies revealed that plasma concentrations of medium- and long-chain acylcarnitines (by-products of incomplete β-oxidation) are elevated in T2DM and insulin resistance. In a previous study, we reported that mixed d,l isomers of C12- or C14-carnitine induced an NF-κB-luciferase reporter gene in RAW 264.7 cells, suggesting potential activation of proinflammatory pathways. Here, we determined whether the physiologically relevant l-acylcarnitines activate classical proinflammatory signaling pathways and if these outcomes involve pattern recognition receptor (PRR)-associated pathways. Acylcarnitines induced the expression of cyclooxygenase-2 in a chain length-dependent manner in RAW 264.7 cells. l-C14 carnitine (5–25 μM), used as a representative acylcarnitine, stimulated the expression and secretion of proinflammatory cytokines in a dose-dependent manner. Furthermore, l-C14 carnitine induced phosphorylation of JNK and ERK, common downstream components of many proinflammatory signaling pathways including PRRs. Knockdown of MyD88, a key cofactor in PRR signaling and inflammation, blunted the proinflammatory effects of acylcarnitine. While these results point to potential involvement of PRRs, l-C14 carnitine promoted IL-8 secretion from human epithelial cells (HCT-116) lacking Toll-like receptors (TLR)2 and -4, and did not activate reporter constructs in TLR overexpression cell models. Thus, acylcarnitines have the potential to activate inflammation, but the specific molecular and tissue target(s) involved remain to be identified.

Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages

“…In contrast, short chain acylcarnitines were relatively decreased in IFN-␥-stimulated Irgm1-deficient BMM. Because LC-AC have pro-inflammatory properties (47)(48)(49)(50)(51), these data reinforce the finding that in IFN-␥-primed Irgm1-deficient macrophages, metabolic changes occur that are proinflammatory and typically only seen in macrophages following activation with LPS. We also exposed the cells to LPS and IFN-␥ to examine how the metabolic changes in IFN-␥-primed, Irgm1-deficient cells might compare with those in fully activated macrophages.…”

Comprehensive Proteomic and Metabolomic Signatures of Nontypeable Haemophilus influenzae-Induced Acute Otitis Media Reveal Bacterial Aerobic Respiration in an Immunosuppressed Environment

“…Of these, 66 showed statistically significant changes because of NTHI infection. Acylcarnitines stimulate proinflammatory responses, in part, through IL-8 (73). However, acylcarnitines were not detected.…”

Long-chain acylcarnitines activate cell stress and myokine release in C2C12myotubes: calcium-dependent and -independent effects

“…Our previous work has shown that long-chain fatty acylcarnitines activate proinflammatory signaling pathways in RAW 264.7 murine macrophages (1,29) and in HCT-116 cells (29), and blunt the insulin signaling pathway in both murine C 2 C 12 and human primary skeletal muscle cells (2). These activities were found to occur at initial extracellular concentrations of C14 carnitine and C16 carnitine as low as 5 M. Thus, whether or not these metabolites contribute to, or exacerbate, disease phenotypes or normal physiological processes remains an open question.…”