Theranostics 2020; 10(20):9230-9248. doi:10.7150/thno.45253

Research Paper

Epigenetic repression of miR-17 contributed to di(2-ethylhexyl) phthalate-triggered insulin resistance by targeting Keap1-Nrf2/miR-200a axis in skeletal muscle

Jie Wei1#✉, Qiongyu Hao3#, Chengkun Chen1, Juan Li1, Xikui Han1, Zhao Lei2, Tao Wang4, Yinan Wang1, Xiang You1, Xiaoxuan Chen2, Huasheng Li1, Yuxin Ding1, Weihao Huang1, Yangyang Hu1, Shuirong Lin1, Heqing Shen2✉, Yi Lin2✉

1. Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen 361102, China.
2. State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China.
3. Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, David Geffen UCLA School of Medicine, and UCLA Jonsson Comprehensive Cancer Center, 1748 E. 118th Street, Los Angeles, CA, 90059, USA.
4. The First Affiliated Hospital of Xiamen University, Xiamen, 361003, China.
#These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Wei J, Hao Q, Chen C, Li J, Han X, Lei Z, Wang T, Wang Y, You X, Chen X, Li H, Ding Y, Huang W, Hu Y, Lin S, Shen H, Lin Y. Epigenetic repression of miR-17 contributed to di(2-ethylhexyl) phthalate-triggered insulin resistance by targeting Keap1-Nrf2/miR-200a axis in skeletal muscle. Theranostics 2020; 10(20):9230-9248. doi:10.7150/thno.45253. Available from https://www.thno.org/v10p9230.htm

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Abstract

Rationale: Skeletal muscle insulin resistance is detectable before type 2 diabetes is diagnosed. Exposure to di(2-ethylhexyl) phthalate (DEHP), a typical environmental endocrine-disrupting chemical, is a novel risk factor for insulin resistance and type 2 diabetes. This study aimed to explore insulin signaling regulatory pathway in skeletal muscle of the DEHP-induced insulin-resistant mice and to investigate potential therapeutic strategies for treating insulin resistance.

Methods: C57BL/6J male mice were exposed to 2 mg/kg/day DEHP for 15 weeks. Whole-body glucose homeostasis, oxidative stress and deregulated miRNA-mediated molecular transduction in skeletal muscle were examined. microRNA (miRNA) interventions based on lentiviruses and adeno-associated viruses 9 (AAV9) were performed.

Results: Dnmt3a-dependent promoter methylation and lncRNA Malat1-related sponge functions cooperatively downregulated miR-17 in DEHP-exposed skeletal muscle cells. DEHP suppressed miR-17 to disrupt the Keap1-Nrf2 redox system and to activate oxidative stress-responsive Txnip in skeletal muscle. Oxidative stress upregulated miR-200a, which directly targets the 3'UTR of Insr and Irs1, leading to hindered insulin signaling and impaired insulin-dependent glucose uptake in skeletal muscle, ultimately promoting the development of insulin resistance. AAV9-induced overexpression of miR-17 and lentivirus-mediated silencing of miR-200a in skeletal muscle ameliorated whole-body insulin resistance in DEHP-exposed mice.

Conclusions: The miR-17/Keap1-Nrf2/miR-200a axis contributed to DEHP-induced insulin resistance. miR-17 is a positive regulator, whereas miR-200a is a negative regulator of insulin signaling in skeletal muscle, and both miRNAs have the potential to become therapeutic targets for preventing and treating insulin resistance or type 2 diabetes.

Keywords: Environmental endocrine-disrupting chemical, Insulin resistance, microRNA, Oxidative stress, Skeletal muscle