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

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.

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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. Available from 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