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Following publication of the original article [1], the author reported the title of this article has been misspelled.
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BACKGROUND: Non-alcoholic fatty liver disease has been associated with increased mRNA expression of FADS2 in the liver and estimated activity of delta-6 desaturase in serum, encoded by the FADS2 gene. Since DNA methylation in the FADS1/2/3 gene cluster has been previously linked with genetic variants and desaturase activities, we now aimed to discover factors regulating DNA methylation of the CpG sites annotated to FADS1/2 genes. METHODS: DNA methylation levels in the CpG sites annotated to FADS2 and FADS1 were analyzed from liver samples of 95 obese participants of the Kuopio Obesity Surgery Study (34 men and 61 women, age 49.5 ± 7.7 years, BMI 43.0 ± 5.7 kg/m2) using the Infinium HumanMethylation450 BeadChip (Illumina). Associations between DNA methylation levels and estimated delta-6 and delta-5 desaturase enzyme activities, liver histology, hepatic mRNA expression, FADS1/2 genotypes, and erythrocyte folate levels were analyzed. RESULTS: We found a negative correlation between DNA methylation levels of cg06781209 and cg07999042 and hepatic FADS2 mRNA expression (both p < 0.05), and with estimated delta-6 desaturase activity based on both liver and serum fatty acids (all p < 0.05). Interestingly, the methylation level of cg07999042 (p = 0.001) but not of cg06781209 (p = 0.874) was associated with FADS2 variant rs174616. CONCLUSIONS: Genetic variants of FADS2 may contribute to the pathogenesis of non-alcoholic fatty liver disease by modifying DNA methylation.
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Metilación de ADN , Ácido Graso Desaturasas/genética , Ácido Graso Desaturasas/metabolismo , Perfilación de la Expresión Génica/métodos , Hígado/enzimología , Enfermedad del Hígado Graso no Alcohólico/genética , Adulto , Islas de CpG , delta-5 Desaturasa de Ácido Graso , Epigénesis Genética , Femenino , Ácido Fólico/sangre , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Análisis de Secuencia de ARN , Regulación hacia ArribaRESUMEN
BACKGROUND: Non-alcoholic steatohepatitis (NASH) is associated with changes in fatty acid (FA) metabolism. However, specific changes in metabolism and hepatic mRNA expression related to NASH independent of simple steatosis, obesity and diet are unknown. METHODS: Liver histology, serum and liver FA composition and estimated enzyme activities based on the FA ratios in cholesteryl esters and triglycerides were assessed in 92 obese participants of the Kuopio Obesity Surgery Study (KOBS) divided to those with normal liver, steatosis or NASH (30 men and 62 women, age 46.8±9.5years (mean±SD), BMI 44.2±6.2kg/m(2)). Plasma FA composition was also investigated in the Metabolic Syndrome in Men (METSIM) Study (n=769), in which serum alanine aminotransferase (ALT) was used as a marker of liver disease. RESULTS: Obese individuals with NASH had higher activity of estimated activities of delta-6 desaturase (D6D, p<0.002) and stearoyl-CoA desaturase 1 (SCD1, p<0.002) and lower activity of delta-5 desaturase (D5D, p<0.002) when compared to individuals with normal liver. Estimated activities of D5D, D6D and SCD1 correlated positively between liver and serum indicating that serum estimates reflected liver metabolism. Accordingly, NASH was associated with higher hepatic mRNA expression of corresponding genes FADS1, FADS2 and SCD. Finally, differences in FA metabolism that associated with NASH in obese individuals were also associated with high ALT in the METSIM Study. CONCLUSIONS: We demonstrated alterations in FA metabolism and endogenous desaturase activities that associate with NASH, independent of obesity and diet. This suggests that changes in endogenous FA metabolism are related to NASH and that they may contribute to the progression of the disease.
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Ácido Graso Desaturasas/metabolismo , Ácidos Grasos/metabolismo , Hígado Graso/metabolismo , Regulación Enzimológica de la Expresión Génica , Hígado/enzimología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Obesidad Mórbida/complicaciones , Adulto , Índice de Masa Corporal , Ésteres del Colesterol/sangre , Ésteres del Colesterol/metabolismo , Estudios de Cohortes , Estudios Transversales , delta-5 Desaturasa de Ácido Graso , Ácido Graso Desaturasas/genética , Ácidos Grasos/sangre , Hígado Graso/complicaciones , Hígado Graso/epidemiología , Hígado Graso/patología , Femenino , Finlandia/epidemiología , Derivación Gástrica , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Hígado/metabolismo , Hígado/patología , Masculino , Síndrome Metabólico/complicaciones , Síndrome Metabólico/epidemiología , Síndrome Metabólico/metabolismo , Síndrome Metabólico/patología , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/patología , Obesidad Mórbida/cirugía , Riesgo , Triglicéridos/sangre , Triglicéridos/metabolismoRESUMEN
Obesity is associated with disturbed lipid metabolism and low-grade inflammation in tissues. The aim of this study was to investigate the association between FA metabolism and adipose tissue (AT) inflammation in the Kuopio Obesity Surgery study. We investigated the association of surgery-induced weight loss and FA desaturase (FADS)1/2 genotypes with serum and AT FA profile and with AT inflammation, measured as interleukin (IL)-1ß and NFκB pathway gene expression, in order to find potential gene-environment interactions. We demonstrated an association between serum levels of saturated and polyunsaturated n-6 FAs, and estimated enzyme activities of FADS1/2 genes with IL-1ß expression in AT both at baseline and at follow-up. Variation in the FADS1/2 genes associated with IL-1ß and NFκB pathway gene expression in SAT after weight reduction, but not at baseline. In addition, the FA composition in subcutaneous and visceral fat correlated with serum FAs, and the associations between serum PUFAs and estimated D6D enzyme activity with AT inflammation were also replicated with corresponding AT FAs and AT inflammation. We conclude that the polymorphism in FADS1/2 genes associates with FA metabolism and AT inflammation, leading to an interaction between weight loss and FADS1/2 genes in the regulation of AT inflammation.
