Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
Horm Metab Res. 2013 Oct;45(11):786-94. doi: 10.1055/s-0033-1348263. Epub 2013 Jun 26.
Obesity and alterations of lipid homeostasis are hallmarks of the metabolic syndrome and largely influenced by the dietary conditions of the individual. Although heritability is considered to be a major risk factor, the almost 40 candidate genes identified by genome-wide association studies (GWAS) so far account for only 5-10% of the observed variance in BMI in human subjects. Alternatively, diet-induced changes of epigenetic gene regulation might be involved in disturbed lipid homeostasis and weight development. The aim of this study was to investigate how a high-carbohydrate diet (HCD; 70 kcal% from carbohydrates, 10 kcal% from fat) or a high-fat diet (HFD; 20 kcal% from carbohydrates, 60 kcal% from fat) affects hepatic expression of genes involved in fatty acid metabolism and if these alterations are correlated to changes in promoter methylation. Expression of stearoyl-CoA desaturase 1 (Scd1) was lower in livers from HFD-fed C57BL/6 J mice compared to HCD-fed animals and correlated inversely with the degree of DNA methylation at 2 distinct, adjacent CpG sites in the Scd1 promoter. In contrast, expression of transcription factors peroxisome proliferator activated receptor alpha and gamma (Ppara, Pparg), and sterol regulatory element binding transcription factor 1 (Srebf1) was not affected. The degree of hepatic Scd1 promoter methylation at these CpG sites correlated positively to fat mass and serum leptin levels, whereas serum ghrelin levels were inversely correlated with methylation at both CpG sites. Taken together, hepatic expression of Scd1 is differentially affected by carbohydrate- and lipid content of the diet. These differences in Scd1 expression are associated with altered promoter methylation, indicating that diets affect lipid metabolism in the liver via epigenetic mechanisms.
肥胖和脂质稳态的改变是代谢综合征的标志，在很大程度上受到个体饮食条件的影响。尽管遗传因素被认为是主要的风险因素，但迄今为止，全基因组关联研究（GWAS）确定的近 40 个候选基因仅占人类 BMI 观察到的变异的 5-10%。相反，饮食诱导的表观遗传基因调控变化可能与脂质稳态和体重发育紊乱有关。本研究旨在探讨高碳水化合物饮食（HCD；碳水化合物占 70%，脂肪占 10%）或高脂肪饮食（HFD；碳水化合物占 20%，脂肪占 60%）如何影响脂肪酸代谢相关基因在肝脏中的表达，以及这些变化是否与启动子甲基化的变化相关。与 HCD 喂养的 C57BL/6 J 小鼠相比，HFD 喂养的小鼠肝脏中硬脂酰辅酶 A 去饱和酶 1（Scd1）的表达降低，并且与 Scd1 启动子中 2 个不同的相邻 CpG 位点的 DNA 甲基化程度呈负相关。相比之下，转录因子过氧化物酶体增殖物激活受体 alpha 和 gamma（Ppara、Pparg）和固醇调节元件结合转录因子 1（Srebf1）的表达不受影响。这些 CpG 位点的肝脏 Scd1 启动子甲基化程度与脂肪质量和血清瘦素水平呈正相关，而血清 ghrelin 水平与两个 CpG 位点的甲基化呈负相关。总之，肝脏 Scd1 的表达受饮食中碳水化合物和脂肪含量的差异影响。Scd1 表达的这些差异与启动子甲基化改变相关，表明饮食通过表观遗传机制影响肝脏的脂质代谢。
