BACKGROUND Adipogenesis, the process whereby preadipocytes differentiate into mature adipocytes, is crucial for maintaining metabolic homeostasis. Cholesterol-lowering statins increase type 2 diabetes (T2D) risk possibly by affecting adipogenesis and insulin resistance but the (epi)genetic mechanisms involved are unknown. Here, we characterised the effects of statin treatment on adipocyte differentiation using in vitro human preadipocyte cell model to identify putative effective genes. RESULTS Statin treatment during adipocyte differentiation caused a reduction in key genes involved in adipogenesis, such as ADIPOQ, GLUT4 and ABCG1. Using Illumina's Infinium '850K' Methylation EPIC array, we found a significant hypomethylation of cg14566882, located in the promoter of the histone deacetylase 9 (HDAC9) gene, in response to two types of statins (atorvastatin and mevastatin), which correlates with an increased HDAC9 mRNA expression. We confirmed that HDAC9 is a transcriptional repressor of the cholesterol efflux ABCG1 gene expression, which is epigenetically modified in obesity and prediabetic states. Thus, we assessed the putative impact of ABCG1 knockdown in mimicking the effect of statin in adipogenesis. ABCG1 KD reduced the expression of key genes involved in adipocyte differentiation and decreased insulin signalling and glucose uptake. In human blood cells from two cohorts, ABCG1 expression was impaired in response to statins, confirming that ABCG1 is targeted in vivo by these drugs. CONCLUSIONS We identified an epigenetic link between adipogenesis and adipose tissue insulin resistance in the context of T2D risk associated with statin use, which has important implications as HDAC9 and ABCG1 are considered potential therapeutic targets for obesity and metabolic diseases.

中文翻译：

---

与脂肪细胞功能障碍相关的组蛋白去乙酰化酶 9 启动子低甲基化是他汀类药物相关的代谢作用。

背景脂肪生成，即前脂肪细胞分化为成熟脂肪细胞的过程，对于维持代谢稳态至关重要。降低胆固醇的他汀类药物可能通过影响脂肪生成和胰岛素抵抗来增加 2 型糖尿病 (T2D) 风险，但所涉及的（表观）遗传机制尚不清楚。在这里，我们使用体外人前脂肪细胞模型来表征他汀类药物治疗对脂肪细胞分化的影响，以确定推定的有效基因。结果 在脂肪细胞分化期间，他汀类药物治疗导致参与脂肪生成的关键基因减少，例如 ADIPOQ、GLUT4 和 ABCG1。使用 Illumina 的 Infinium '850K' 甲基化 EPIC 阵列，我们发现 cg14566882 显着低甲基化，位于组蛋白去乙酰化酶 9 (HDAC9) 基因的启动子中，响应两种类型的他汀类药物（阿托伐他汀和美伐他汀），这与 HDAC9 mRNA 表达增加有关。我们证实 HDAC9 是胆固醇外流 ABCG1 基因表达的转录抑制因子，其在肥胖和糖尿病前期状态中经过表观遗传修饰。因此，我们评估了 ABCG1 敲低在模拟他汀类药物在脂肪生成中的作用的假定影响。ABCG1 KD 降低了参与脂肪细胞分化的关键基因的表达，并降低了胰岛素信号传导和葡萄糖摄取。在来自两个队列的人类血细胞中，ABCG1 表达因他汀类药物而受损，证实这些药物在体内靶向 ABCG1。结论 在与他汀类药物使用相关的 T2D 风险背景下，我们确定了脂肪生成和脂肪组织胰岛素抵抗之间的表观遗传联系，