RESUMEN
We previously showed that conjugated linoleic acid (CLA) increases 15-keto-dihydro-prostaglandin F2alpha, a marker for cyclooxygenase-mediated lipid peroxidation and thus an indicator of cyclooxygenase-mediated inflammation. The aim of the present study was to investigate the effects of CLA on other indicators of inflammation in human subjects, including C-reactive protein, TNF-alpha, TNF-alpha receptors 1 and 2, and vascular cell adhesion molecule-1. In a double-blind, placebo-controlled study, fifty-three human subjects were supplemented with a mixture (4.2 g/d) of the isomers cis-9,trans-11 CLA and trans-10,cis-12 CLA or control oil for 3 months. CLA supplementation increased levels of C-reactive protein (P=0.003) compared with the control group. However, no changes in TNF-alpha, TNF-alpha receptors 1 and 2, and vascular cell adhesion molecule-1 were detected.
Asunto(s)
Proteína C-Reactiva/análisis , Ácidos Linoleicos Conjugados/farmacología , Adulto , Biomarcadores/sangre , Dinoprost/análogos & derivados , Dinoprost/sangre , Método Doble Ciego , Femenino , Humanos , Inflamación/sangre , Masculino , Persona de Mediana Edad , Receptores Tipo I de Factores de Necrosis Tumoral/sangre , Receptores Tipo II del Factor de Necrosis Tumoral/sangre , Análisis de Regresión , Factor de Necrosis Tumoral alfa/análisis , Molécula 1 de Adhesión Celular Vascular/sangreRESUMEN
BACKGROUND: Accumulation and oxidation of LDL are believed to be important initiating factors in atherosclerosis. Oxidized LDL is recognized by the immune system, and animal studies have suggested that these immune responses have a protective effect against atherosclerosis. Aldehyde-modified peptide sequences in apolipoprotein B-100 (apoB-100) are major targets for these immune responses. METHODS AND RESULTS: Human IgG1 antibodies against 2 malondialdehyde (MDA)-modified apoB-100 peptide sequences were produced through screening of a single-chain antibody-fragment library and subsequent cloning into a pcDNA3 vector. Three weekly doses of these antibodies were injected into male apoE-/- mice. Phosphate-buffered saline and human IgG1 antibodies against fluorescein isothiocyanate were used as controls. One of the IgG1 antibodies significantly and dose-dependently reduced the extent of atherosclerosis as well as the plaque content of oxidized LDL epitopes and macrophages. In cell culture studies, human monocytes were incubated with native LDL or oxidized LDL, in the presence of antibodies. The same antibody induced an increase in monocyte binding and uptake of oxidized LDL. CONCLUSIONS: These findings suggest that antibodies are important mediators of atheroprotective immune responses directed to oxidized LDL. Thus, passive immunization against MDA-modified apoB-100 peptide sequences may represent a novel therapeutic approach for prevention and treatment of cardiovascular disease.
Asunto(s)
Apolipoproteínas B/inmunología , Arteriosclerosis/prevención & control , Inmunización Pasiva , Fragmentos de Inmunoglobulinas/uso terapéutico , Inmunoglobulina G/uso terapéutico , Región Variable de Inmunoglobulina/uso terapéutico , Lipoproteínas LDL/metabolismo , Secuencia de Aminoácidos , Animales , Apolipoproteína B-100 , Apolipoproteínas B/química , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Arteriosclerosis/patología , Evaluación Preclínica de Medicamentos , Humanos , Fragmentos de Inmunoglobulinas/genética , Fragmentos de Inmunoglobulinas/inmunología , Inmunoglobulina G/genética , Inmunoglobulina G/inmunología , Región Variable de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/inmunología , Cadenas lambda de Inmunoglobulina/genética , Lipoproteínas LDL/farmacología , Macrófagos/patología , Masculino , Malondialdehído/química , Malondialdehído/inmunología , Ratones , Ratones Noqueados , Datos de Secuencia Molecular , Monocitos/metabolismo , Fragmentos de Péptidos/química , Fragmentos de Péptidos/inmunología , Proteínas Recombinantes de Fusión/inmunología , Proteínas Recombinantes de Fusión/uso terapéuticoRESUMEN
BACKGROUND: Conjugated linoleic acids (CLAs), a group of fatty acids shown to have beneficial effects in animals, are also used as weight loss supplements. Recently, we reported that the t10c12 CLA-isomer caused insulin resistance in abdominally obese men via unknown mechanisms. The aim of the present study was to examine whether CLA has isomer-specific effects on oxidative stress or inflammatory biomarkers and to investigate the relationship between these factors and induced insulin resistance. METHODS AND RESULTS: In a double-blind placebo-controlled trial, 60 men with metabolic syndrome were randomized to one of 3 groups receiving t10c12 CLA, a CLA mixture, or placebo for 12 weeks. Insulin sensitivity (euglycemic clamp), serum lipids, in vivo lipid peroxidation (determined as urinary 8-iso-PGF(2alpha) [F2-isoprostanes]), 15-ketodihydro PGF(2alpha), plasma vitamin E, plasma C-reactive protein, tumor necrosis factor-alpha, and interleukin-6 were assessed before and after treatment. Supplementation with t10c12 CLA markedly increased 8-iso-PGF(2alpha) (578%) and C-reactive protein (110%) compared with placebo (P<0.0001 and P<0.01, respectively) and independent of changes in hyperglycemia or dyslipidemia. The increases in 8-iso-PGF(2alpha), but not in C-reactive protein, were significantly and independently related to aggravated insulin resistance. Oxidative stress was related to increased vitamin E levels, suggesting a compensatory mechanism. CONCLUSIONS: t10c12 CLA supplementation increases oxidative stress and inflammatory biomarkers in obese men. The oxidative stress seems closely related to induced insulin resistance, suggesting a link between the fatty acid-induced lipid peroxidation seen in the present study and insulin resistance. These unfavorable effects of t10c12 CLA might be of clinical importance with regard to cardiovascular disease, in consideration of the widespread use of dietary supplements containing this fatty acid.