Abstract
BackgroundAdipogenesis, 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.ResultsStatin 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.ConclusionsWe 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.
Highlights
Adipogenesis, the process whereby preadipocytes differentiate into mature adipocytes, is crucial for maintaining metabolic homeostasis
Statin treatment reduced adipogenesis and insulin signalling The Simpson-Golabi-Behmel syndrome (SGBS) human preadipocyte cell line was used in this study as an in vitro model for adipocyte differentiation
We found a decrease in lipid in statin-treated SGBS cells when compared to dimethyl sulfoxide (DMSO)-vehicle controls (p < 0.05; Fig. 1b)
Summary
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. Adipose expansion occurs as a result of cellular hypertrophy, i.e. the increase in size of the adipocyte and/or de novo adipogenesis, which is the production of new mature adipocytes from residing preadipocytes [2,3,4]. Epigenome-wide association studies (EWAS) have found that hypermethylation within one of these genes involved in adipogenesis, ABCG1, was associated with increased body mass index (BMI), insulin resistance and T2D risk [12,13,14,15], opening avenues in the elucidation of the links between adipogenesis and metabolic diseases
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