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Theranostics 2018; 8(20):5593-5609. doi:10.7150/thno.27425 This issue Cite

Research Paper

miR-125a-5p ameliorates hepatic glycolipid metabolism disorder in type 2 diabetes mellitus through targeting of STAT3

Lina Xu, Yue Li, Lianhong Yin, Yan Qi, Huijun Sun, Pengyuan Sun, Ming Xu, Zeyao Tang, Jinyong Peng✉

College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China.

✉ Corresponding author: Dr. Jinyong Peng, College of Pharmacy, Dalian Medical University, Dalian, China. Tel.: +86 411 8611 0411 Fax: +86 411 8611 0411 Email: jinyongpeng2005com

Citation:
Xu L, Li Y, Yin L, Qi Y, Sun H, Sun P, Xu M, Tang Z, Peng J. miR-125a-5p ameliorates hepatic glycolipid metabolism disorder in type 2 diabetes mellitus through targeting of STAT3. Theranostics 2018; 8(20):5593-5609. doi:10.7150/thno.27425. https://www.thno.org/v08p5593.htm
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Abstract

Graphic abstract

Glycolipid metabolic disorder is an important cause for the development of type 2 diabetes mellitus (T2DM). Clarification of the molecular mechanism of metabolic disorder and exploration of drug targets are crucial for the treatment of T2DM.

Methods: We examined miR-125a-5p levels in palmitic acid-induced AML12 cells and the livers of type 2 diabetic rats and mice, and then validated its target gene. Through gain- and loss-of-function studies, the effects of miR-125a-5p via targeting of STAT3 on regulating glycolipid metabolism were further illustrated in vitro and in vivo.

Results: We found that miR-125a-5p was significantly decreased in the livers of diabetic mice and rats, and STAT3 was identified as the target gene of miR-125a-5p. Overexpression of miR-125a-5p in C57BL/6 mice decreased STAT3 level and downregulated the expression levels of p-STAT3 and SOCS3. Consequently, SREBP-1c-mediated lipogenesis pathway was inhibited, and PI3K/AKT pathway was activated. Moreover, silencing of miR-125a-5p significantly increased the expression levels of STAT3, p-STAT3 and SOCS3, thus activating SREBP-1c pathway and suppressing PI3K/AKT pathway. Therefore, hyperglycemia, hyperlipidemia and decreased liver glycogen appeared in C57BL/6 mice. In palmitic acid-induced AML12 cells, miR-125a-5p mimic markedly increased glucose consumption and uptake and decreased the accumulation of lipid droplets by regulating STAT3 signaling pathway. Consistently, miR-125a-5p overexpression obviously inhibited STAT3 expression in diabetic KK-Ay mice, thereby decreasing blood glucose and lipid levels, increasing hepatic glycogen content, and decreasing accumulation of hepatic lipid droplets in diabetic mice. Furthermore, inhibition of miR-125a-5p in KK-Ay mice aggravated glycolipid metabolism dysfunction through regulating STAT3.

Conclusions: Our results confirmed that miR-125a-5p should be considered as a regulator of glycolipid metabolism in T2DM, which can inhibit hepatic lipogenesis and gluconeogenesis and elevate glycogen synthesis by targeting STAT3.

Keywords: type 2 diabetes mellitus, metabolic disorder, microRNA, miR-125a-5p, STAT3

Citation styles

APA
Xu, L., Li, Y., Yin, L., Qi, Y., Sun, H., Sun, P., Xu, M., Tang, Z., Peng, J. (2018). miR-125a-5p ameliorates hepatic glycolipid metabolism disorder in type 2 diabetes mellitus through targeting of STAT3. Theranostics, 8(20), 5593-5609. https://doi.org/10.7150/thno.27425.

ACS
Xu, L.; Li, Y.; Yin, L.; Qi, Y.; Sun, H.; Sun, P.; Xu, M.; Tang, Z.; Peng, J. miR-125a-5p ameliorates hepatic glycolipid metabolism disorder in type 2 diabetes mellitus through targeting of STAT3. Theranostics 2018, 8 (20), 5593-5609. DOI: 10.7150/thno.27425.

NLM
Xu L, Li Y, Yin L, Qi Y, Sun H, Sun P, Xu M, Tang Z, Peng J. miR-125a-5p ameliorates hepatic glycolipid metabolism disorder in type 2 diabetes mellitus through targeting of STAT3. Theranostics 2018; 8(20):5593-5609. doi:10.7150/thno.27425. https://www.thno.org/v08p5593.htm

CSE
Xu L, Li Y, Yin L, Qi Y, Sun H, Sun P, Xu M, Tang Z, Peng J. 2018. miR-125a-5p ameliorates hepatic glycolipid metabolism disorder in type 2 diabetes mellitus through targeting of STAT3. Theranostics. 8(20):5593-5609.

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