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

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.

SUBMITTER: Wei J

PROVIDER: S-EPMC7415800 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Wei Jie J Hao Qiongyu Q Chen Chengkun C Li Juan J Han Xikui X Lei Zhao Z Wang Tao T Wang Yinan Y You Xiang X Chen Xiaoxuan X Li Huasheng H Ding Yuxin Y Huang Weihao W Hu Yangyang Y Lin Shuirong S Shen Heqing H Lin Yi Y

Theranostics 20200723 20

<b>Rationale:</b> 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. <b>Methods:</b> ...[more]

PMID: 32802189

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Project description:Oxidative stress is a critical factor in nonalcoholic fatty liver disease pathogenesis. MicroRNA-200a (miR-200a) is reported to target Kelch-like ECH-associated protein 1 (Keap1), which regulates nuclear factor erythroid 2-related factor 2 (Nrf2) anti-oxidant pathway. Polydatin (3,4',5-trihydroxy-stilbene-3-?-D-glucoside), a polyphenol found in the rhizome of Polygonum cuspidatum, have anti-oxidative, anti-inflammatory and anti-hyperlipidemic effects. However, whether miR-200a controls Keap1/Nrf2 pathway in fructose-induced liver inflammation and lipid deposition and the blockade of polydatin are still not clear. Here, we detected miR-200a down-regulation, Keap1 up-regulation, Nrf2 antioxidant pathway inactivation, ROS-driven thioredoxin-interacting protein (TXNIP) over-expression, NOD-like receptor (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome activation and dysregulation of peroxisome proliferator activated receptor-? (PPAR-?), carnitine palmitoyl transferase-1 (CPT-1), sterol regulatory element binging protein 1 (SREBP-1) and stearoyl-CoA desaturase-1 (SCD-1) in rat livers, BRL-3A and HepG2 cells under high fructose induction. Furthermore, the data from the treatment or transfection of miR-200a minic, Keap1 and TXNIP siRNA, Nrf2 activator and ROS inhibitor demonstrated that fructose-induced miR-200a low-expression increased Keap1 to block Nrf2 antioxidant pathway, and then enhanced ROS-driven TXNIP to activate NLRP3 inflammasome and disturb lipid metabolism-related proteins, causing inflammation and lipid deposition in BRL-3A cells. We also found that polydatin up-regulated miR-200a to inhibit Keap1 and activate Nrf2 antioxidant pathway, resulting in attenuation of these disturbances in these animal and cell models. These findings provide a novel pathological mechanism of fructose-induced redox status imbalance and suggest that the enhancement of miR-200a to control Keap1/Nrf2 pathway by polydatin is a therapeutic strategy for fructose-associated liver inflammation and lipid deposition.

Project description:Allergic rhinitis (AR) is a common chronic inflammatory disease of the upper respiratory tract. Di(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer and belongs to environmental endocrine disruptors (EDCs). It can be entered the human body which is harmful to health. The relationship between DEHP and AR is still inconclusive. This study aims to investigate the effect of environmental pollutants DEHP on AR. By examining DEHP metabolites in the urine of AR patients and building an AR model. 24 BALB/c mice were used as the study subjects, and ovalbumin (OVA) and DEHP (3 mg/kg/body) were used for intragastric administration. They were divided into control group, DEHP group, OVA group and OVA?+?DEHP group. Examination, behavioral scoring, inflammatory factor testing, oxidative stress testing, detection of aryl hydrocarbon receptor (AhR) and signaling pathways CYP1A1 and CYP1B1 related proteins and mRNA. The concentrations of 3 metabolites of DEHP (MEHHP, MEOHP, and MEHP) in urine of AR patients were higher. And HE-staining showed that for the control group, many chronic inflammatory cell infiltration and nasal mucosal destruction were observed in the OVA?+?DEHP group and were more severe than the OVA group. Allergic symptom scores were obtained from sneezing, scratching, number of scratching, and nose flow. The scores of the OVA group and the OVA?+?DEHP group were higher than 7 points. Serum ELISA and nasal mucosal oxidative stress tests are more serious in the OVA?+?DEHP group. The expression of AhR protein and its mRNA was increased in the DEHP group, OVA group and OVA?+?DEHP group. The OVA?+?DEHP group was more significant in the OVA group and DEHP group. And the mRNAs of the AhR-related signaling pathways CYP1A1 and CYP1B1 were also more prominent in the OVA?+?DEHP group. DEHP may aggravate its inflammatory response through the AhR pathway closely related to the environment. When combined with OVA, DEHP can further aggravate the OVA-induced nasal inflammatory response and make the nasal cavity have undergone severe changes, and many inflammatory cells have infiltrated. DEHP has shown an adjuvant effect, and the AhR-related signaling pathways CYP1A1 and CYP1B1 may be critical.

Dataset Information

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

Publications

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

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