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

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.

MiR-455 targeting SOCS3 improve liver lipid disorders in diabetic mice

“…SOCS3 has been reported involving in the progress of various diseases such as autoimmune diseases [31], cardiovascular diseases [32], metabolic diseases [33] and tumours [34], which is responsive to an increase in IL-6 and plays a negative regulatory role in cytokine signalling [12]. It has been shown that miR-19a-3p can promote cell proliferation and insulin secretion by targeting SOCS3 [13], overexpression of miR-125a-5p also inhibit the expression of SOCS3 to improve glycolipid metabolism in the liver [14]. In our study, miR-455 can significantly reduce serum and liver TG level without affecting BW and blood glucose, the probable reason is that the cycle of the experiment is not long enough to significantly improve blood glucose.…”

“…At the same time, SOCS3 also plays an important role in the regulation of metabolism. The overexpression of miR-19a [13] and miR-125a [14] could improve the metabolism of glucose and lipid through targeting SOCS3. We found that miR-455 ameliorated the lipid metabolic disorder of liver in db/db mice and this improvement may be caused by inhibition of SOCS3.…”

Transplantation of brown adipose tissue up-regulates miR-99a to ameliorate liver metabolic disorders in diabetic mice by targeting NOX4

“…Furthermore, luciferase reporter gene experiments confirmed that miR-99a targets and regulates the expression of NOX4. There were also many in vitro studies on miRNAs involved in the regulation of lipid metabolism, such as miR-146a-5p [48], miR-125a-5p [49] and so on. Therefore, there might be multiple miRNAs involved in the regulation of hepatic lipid metabolism, and our findings could provide some help for the treatment of NAFLD.…”

Spatholobus suberectus extract suppresses proliferation and EMT, and promotes apoptosis in palmitic acid induced vascular endothelial cells by inhibiting LncRNA MALAT1 via VEGF signaling pathway

“…There are five members in VEGF signaling pathway: VEGF-A, VEGF-B, VEGF-C, VEGF-D and placental growth factor (PIGF). VEGFR-2 (KDR/Flk-1) is the primary function receptor which is mainly expressed in vascular endothelial cells [4].It was reported previously that VEGF signaling pathway was activated in glucose-induced HUVECs [23].…”