Histone deacetylase 9 promoter hypomethylation associated with adipocyte dysfunction is a statin-related metabolic effect
Author(s)
Type
Journal Article
Abstract
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.
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.
Date Issued
2020-05-14
Date Acceptance
2020-04-28
Citation
Clinical Epigenetics, 2020, 12 (1), pp.1-12
ISSN
1868-7083
Publisher
BioMed Central
Start Page
1
End Page
12
Journal / Book Title
Clinical Epigenetics
Volume
12
Issue
1
Copyright Statement
© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,
which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
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The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the
data made available in this article, unless otherwise stated in a credit line to the data.
which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if
changes were made. The images or other third party material in this article are included in the article's Creative Commons
licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons
licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain
permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the
data made available in this article, unless otherwise stated in a credit line to the data.
License URL
Identifier
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Subjects
Science & Technology
Life Sciences & Biomedicine
Oncology
Genetics & Heredity
Adipogenesis
Methylation
ABCG1
HDAC9
EPIGENOME-WIDE ASSOCIATION
DNA METHYLATION
ADIPOSE-TISSUE
EXPRESSION
INSULIN
BLOOD
SIZE
MACROPHAGES
PACKAGE
TARGETS
Publication Status
Published
Article Number
ARTN 68
Date Publish Online
2020-05-14