Interactions of acyl carnitines with model membranes

Ho, Jet; Duclos, R.; Hamilton, James A.

doi:10.1194/jlr.m200137-jlr200

Cited by 49 publications

(33 citation statements)

References 50 publications

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“…A more recent paper using 13 C-NMR suggested that C14-carnitine can incorporate into model membranes at high rates but does not cause disorganization of bilayer structure. Therefore, the authors hypothesized that acylcarnitine effects are not merely the result of membrane disruption but by interference with membrane functions or signaling (4). However, while the responses that we observed may be in part due to a "detergent effect," this is unlikely to explain the specific activation of signaling pathways including the necessity of the downstream signaling component MyD88.…”

Section: Discussioncontrasting

confidence: 45%

Acylcarnitines activate proinflammatory signaling pathways

Rutkowsky

Knotts

Ono‐Moore

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

232

204

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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.

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Section: Discussioncontrasting

confidence: 45%

Acylcarnitines activate proinflammatory signaling pathways

Rutkowsky

Knotts

Ono‐Moore

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

232

204

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“…Although diffusion of fatty acids into mitochondria is largely regulated by the transporter enzyme carnitine palmitoyltransferase 1, such diffusion can also occur independent of this mechanism (13). High IMCL levels and high degrees of lipid unsaturation in the muscle of insulin-resistant and diabetic individuals may increase lipid diffusion into the mitochondria in type 2 diabetes (31).…”

Section: Discussionmentioning

confidence: 99%

Distinct patterns of fat metabolism in skeletal muscle of normal-weight, overweight, and obese humans

Velan¹,

Said²,

Durst³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Velan SS, Said N, Durst C, Frisbee S, Frisbee J, Raylman RR, Thomas MA, Rajendran VM, Spencer RG, Alway SE. Distinct patterns of fat metabolism in skeletal muscle of normal-weight, overweight, and obese humans. Am J Physiol Regul Integr Comp Physiol 295: R1060 -R1065, 2008. First published July 30, 2008 doi:10.1152/ajpregu.90367.2008The link between body weight, lipid metabolism, and health risks is poorly understood and difficult to study. Magnetic resonance spectroscopy (MRS) permits noninvasive investigation of lipid metabolism. We extended existing two-dimensional MRS techniques to permit quantification of intra-and extramyocellular lipid (IMCL and EMCL, respectively) compartments and their degree of unsaturation in human subjects and correlated these results with body mass index (BMI). Using muscle creatine for normalization, we observed a statistically significant (P Ͻ 0.01) increase in the IMCL-to-creatine ratio with BMI (n ϭ 8 subjects per group): 5.9 Ϯ 1.7 at BMI Ͻ 25, 10.9 Ϯ 1.82 at 25 Ͻ BMI Ͻ 30, and 13.1 Ϯ 0.87 at BMI Ͼ 30. Similarly, the degree of IMCL unsaturation decreased significantly (P Ͻ 0.01) with BMI: 1.51 Ϯ 0.08 at BMI Ͻ 25, 1.30 Ϯ 0.11 at 25 Ͻ BMI Ͻ 30, and 0.90 Ϯ 0.14 at BMI Ͼ 30. We conclude that important aspects of lipid metabolism can be evaluated by two-dimensional MRS and propose that degree of unsaturation measured noninvasively may serve as a biomarker for lipid metabolic defects associated with obesity. magnetic resonance spectroscopy; lipid unsaturation; intramyocellular lipid; extramyocellular lipid THE AMOUNT OF BODY FAT is a risk factor for several obesityrelated disorders. Obesity is a known risk factor for the development of insulin resistance and diabetes and is a key component of metabolic syndrome. The causal relationship between increased dyslipidemia and adiposity and impaired glucose homeostasis is unclear, although it is known that lipid oversupply to the organs primarily involved in glucose homeostasis, that is, muscle, liver, and pancreas, leads to impaired insulin function in those tissues (22).Previous studies showed that intramyocellular lipid (IMCL) is increased with obesity and in non-insulin-dependent diabetes mellitus (9,11,15). It has been suggested that increased visceral adiposity and reduced lipid oxidation might contribute to the increase in IMCL (18). Thus the ability to monitor the IMCL pool and its properties noninvasively by magnetic resonance spectroscopy (MRS) has been an important development (4, 28). The correlation between the magnitude of the IMCL pool, as determined by MRS studies, and insulin resistance, diabetes, and disorders of lipid metabolism has been previously demonstrated (2,3,32,33). Nevertheless, quantification of IMCL and extramyocellular lipid (EMCL) by MRS remains highly problematic (32). The ability to distinguish IMCL from EMCL is based on their different bulk magnetic susceptibility effects due to their geometric arrangements within muscle, which leads to a spectroscopic frequency separation between the two pools; this sepa...

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“…Etomoxir, an inhibitor of CPT-1, or conditions of an abundance of fatty acid supply to mitochondria, triggers an up-regulation of UCP3 in human muscle (Schrauwen et al 2002). The fatty acids that are not oxidized become trapped as fatty acid anions inside the mitochondrial matrix, where reactive oxygen species (ROS) are formed (Ho et al 2002). UCP3 may be involved in the protection of mitochondria against lipid-induced oxidative damage by facilitating the transport of nonmetabolized fatty acids and lipid peroxides from the mitochondrial matrix.…”

Section: Integration Of Omic Technologies and Organotypic Translationmentioning

confidence: 99%

Characterization of Hepatic Mitochondrial Injury Induced by Fatty Acid Oxidation Inhibitors

Vickers

2009

Toxicol Pathol

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Impairment of liver mitochondrial β-oxidation is an important mechanism of drug-induced liver injury. Four inhibitors of fatty acid oxidation were compared in short-term rat in vivo studies in which the rats were administered one or four doses. The hepatocellular vacuolation represented ultrastructural mitochondrial changes. Urine nuclear magnetic resonance (NMR) spectroscopy revealed that both FOX988 and SDZ51-641 induced a persistent dicarboxylic aciduria, suggesting an inhibition of mitochondrial β-oxidation and incomplete fatty acid metabolism. Etomoxir caused minimal mitochondrial ultrastructural changes and induced only transient dicarboxylic aciduria. CPI975 served as a negative control, in that there were no significant perturbations to the mitochondrial ultrastructural morphology or in the urine NMR composition; however, compound exposure was confirmed by the up-regulation of liver gene expression compared to vehicle control. The liver gene expression changes that were altered by the compounds were indicative of mitochondria, general and oxidative stress, and peroxisomal enzymes involved in β-oxidation, suggestive of a compensatory response to the inhibition in the mitochondria. In addition, both FOX988 and SDZ51-641 up-regulated ribosomal genes associated with apoptosis, as well as p53 pathways linked with apoptosis. In summary, metabonomics and liver gene expression provided mechanistic information on mitochondrial dysfunction and impaired fatty acid oxidation to further define the clinical pathology and histopathology findings of hepatotoxicity.

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Interactions of acyl carnitines with model membranes

Cited by 49 publications

References 50 publications

Acylcarnitines activate proinflammatory signaling pathways

Acylcarnitines activate proinflammatory signaling pathways

Distinct patterns of fat metabolism in skeletal muscle of normal-weight, overweight, and obese humans

Characterization of Hepatic Mitochondrial Injury Induced by Fatty Acid Oxidation Inhibitors

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