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, 11 (5), 2440-2449
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MicroRNA-802 Regulates Hepatic Insulin Sensitivity and Glucose Metabolism

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MicroRNA-802 Regulates Hepatic Insulin Sensitivity and Glucose Metabolism

Yun-Feng Zhen et al. Int J Clin Exp Pathol.

Abstract

The expression level of microRNA-802 (miR-802) is increased in livers of high-fat diet (HFD)-fed mice and obese human subjects; however, the function of miR-802 in the development of obesity-associated insulin resistance remains incompletely understood. Here we studied the potential role of miR-802 in regulating hepatic glucose metabolism and insulin sensitivity. Mice were fed either a standard chow diet or HFD for 12 weeks, and then the HFD mice were infected by injection with an adeno-associated virus expressing miR-802 or miR-802-SP. Six weeks after the injection, we measured blood glucose, plasma insulin, and insulin sensitivity in the mice. In addition, hepatic glucose levels and PI3K-Akt pathway gene expression were analyzed. Adeno-associated viral-mediated overexpression of miR-802 in the livers of HFD mice caused impaired glucose homeostasis and insulin sensitivity, thus giving rise to decreased protein level of pAkts473 and pPI3K, and increased protein levels of pPTEN, G6PC, and GluT2. In contrast, loss of miR-802 function in the liver of HFD mice led to increased pAkts473 and pPI3K, and decreased levels of pPTEN, G6PC, and GluT2, thereby improving glucose metabolism and insulin resistance. Our findings confirmed MiR-802 as a regulator of liver glucose metabolism and insulin signaling.

Keywords: glucose metabolism; hepatic; high-fat diet; insulin resistance; microRNA-802.

Conflict of interest statement

None.

Figures

Figure 1
Figure 1
The effect of HFD on insulin resistance and increased hepatic expression of miR-802. Mice were fed with HFD or normal control diets for 12 weeks. Measurements were performed during the course of the HFD, as shown below (n = 7). A. Total BW. B. Fasting blood glucose. C. Average daily calorie intake. D. GTT, performed after 11 weeks of HFD. E. Fasting plasma insulin. F. AUC. G. Quicki. H. QRT-PCR analysis of miR-802 expression in the liver of HFD mice and controls. Data are shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.005, 2-tailed Student’s t test (B-K).
Figure 2
Figure 2
Hepatic overexpression of miR-802 aggravated HFD-induced insulin resistance and glucose intolerance in the liver (n = 6). Mice were fed with HFD for 12 weeks, and then infected with an adeno-associated virus expressing miR-802 or AAV-Con. Measurements were performed 6 weeks after the injections, as shown below. A. Expression of AAV in the liver, as shown by fluorescence microscopy (mag, 200×). B. QRT-PCR analysis of miR-802 expression in the liver of AAV-miR-802 mice and AAV-GFP controls. C. Total BW. D. GTT, 6 weeks after injection of AAV. E. AUC. F. Fasting plasma insulin. G. QUICKI. Data are shown as mean ± SEM. *P < 0.05, **P < 0.01 vs. Con mice, #P < 0.05, ##P < 0.01 vs. AAV-GFP mice; 2-tailed Student’s t test.
Figure 3
Figure 3
Inhibition of hepatic expression of miR-802 ameliorated insulin resistance in HFD-fed mice. Mice were fed with HFD for 12 weeks, and then infected with an adeno-associated virus expressing miR-802 sponges or AAV-NC. Measurements were performed 6 weeks after the injections, as shown below. A. Expression of AAV in the liver under fluorescence microscopy. B. QRT-PCR analysis of miR-802 expression in the liver of AAV-SP-miR-802 mice and AAV-NC controls. C. Total BW. D. GTT, after 18 weeks of HFD. E. AUC. F. Fasting plasma insulin. G. QUICKI. Data are shown as mean ± SEM. *P < 0.05 vs. Con mice; #P < 0.05 vs. AAV-NC and HFD group mice, 2-tailed Student’s t test.
Figure 4
Figure 4
The effect of miR-802 on PI3K-Akt signaling in HFD mice. Mice were fed with HFD for 12 weeks, and then infected with an adeno-associated viral vector encoding green fluorescent protein (AAV-GFP/NC), miR-802, or miR-802 sponges (n = 6). (A, B) The expression levels of phosphoinositide-3-kinase (PI3K), PTEN, AKT, G6PC, and GluT2 were determined by quantitative real-time-polymerase chain reaction (RT-PCR) (A) and Western blotting (B). Phosphorylation levels of PI3K, PTEN, and AKT were assayed by Western blotting (B). (C) Densitometric analysis of protein expression. (D) Concentrations of hepatic glycogen. Data are shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.005 vs. Con mice, #P < 0.05, ##P < 0.01, ###P < 0.005 vs. AAV-GFP mice, ΔP < 0.05, ΔΔP < 0.01, ΔΔΔP < 0.005 vs. AAV-NC mice, 2-tailed Student’s t test.
Figure 5
Figure 5
MiR-802 regulated hepatic fatty acid metabolism in HFD mice. Mice were fed with HFD for 12 weeks, and then infected with adeno-associated viral vector encoding green fluorescent protein (AAV-(NC)-Con), miR-802, or miR-802 sponges (n = 6). A. Levels of plasma triglyceride (TG). B. Levels of hepatic triglyceride. C. Levels of plasma total cholesterol (TC). D. Histological analysis of liver sections from HFD-fed mice infected with adeno-associated viral vector (AAV-(NC)/GFP), miR-802, or miR-802-SP (HE, × 200). Data are shown as mean ± SEM. ***P < 0.005 vs. Con; #P < 0.05, ###P < 0.005 vs. AAV-GFP group; ΔP < 0.05 vs. AAV-NC group, 2-tailed Student’s t test.

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