miR‑338‑3p mediates gluconeogenesis via targeting of PP4R1 in hepatocytes

Wang,Shuyue; Li,Linfang; Chen,Xiehui; Huang,Xiuqing; Liu,Jin; Sun,Xuelin; Zhang,Yang; Shen,Tao; Guo,Jun; Man,Yong; Tang,Weiqing; Dou,Lin; Li,Jian

doi:10.3892/mmr.2018.9400

miR‑338‑3p mediates gluconeogenesis via targeting of PP4R1 in hepatocytes

Authors:
- Shuyue Wang
- Linfang Li
- Xiehui Chen
- Xiuqing Huang
- Jin Liu
- Xuelin Sun
- Yang Zhang
- Tao Shen
- Jun Guo
- Yong Man
- Weiqing Tang
- Lin Dou
- Jian Li
View Affiliations

Affiliations: The MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing 100730, P.R. China, Department of Geriatrics Cardiovascular Medicine, Shenzhen Sun Yat‑Sen Cardiovascular Hospital, Shenzhen, Guangdong 518112, P.R. China, College of Life Sciences, Beijing Normal University, Beijing 100875, P.R. China
Published online on: August 17, 2018 https://doi.org/10.3892/mmr.2018.9400
Pages: 4129-4137

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Hyperglycaemia is a characteristic of type 2 diabetes. In hepatocytes, impaired insulin sensitivity leads to increased gluconeogenesis and decreased glycogenesis. MicroRNA (miR)‑338‑3p is associated with tumour necrosis factor (TNF)‑α‑induced suppression of hepatic glycogenesis via regulation of protein phosphatase 4 regulatory subunit 1 (PP4R1). However, the effect of miR‑338‑3p on gluconeogenesis in hepatocytes remains unknown. In a previous study, it was demonstrated that miR‑338‑3p is downregulated in the livers of mice and in mouse HEPA1‑6 hepatocytes following treatment with TNF‑α. In the present study, the effect of miR‑338‑3p on TNF‑α‑induced gluconeogenesis in hepatocytes was investigated. The levels of phosphorylated‑FOXO1/FOXO1, phosphoenolpyruvate carboxykinase (PEPCK), peroxisome proliferator‑activated receptor γ coactivator (PGC‑1α) and glucose‑6‑phosphatase (G6Pase) were measured by western blotting. The mRNA levels of PEPCK, PGC‑1α and G6Pase were determined by quantitative polymerase chain reaction. Pyruvate tolerance testing was used to determine the gluconeogenesis of mouse livers. The results demonstrated that treatment with TNF‑α resulted in increased levels of gluconeogenesis in the livers of mice and decreased miR‑338‑3p expression levels in HEPA1‑6 cells. Overexpression of miR‑338‑3p reversed TNF‑α‑induced glucose production via enhancement of phosphorylated forkhead box O1 levels and downregulation of the expression levels of genes associated with gluconeogenesis, including peroxisome proliferator‑activated receptor γ coactivator‑1α, phosphoenolpyruvate carboxykinase and glucose‑6‑phosphatase. However, inhibition of miR‑338‑3p expression was revealed to enhance gluconeogenesis in the livers of mice and in HEPA1‑6 cells. Furthermore, downregulation of PP4R1 was revealed to attenuate the effect on glucose production following treatment with miR‑338‑3p inhibitors. In conclusion, the results of the present study revealed that miR‑338‑3p may be involved in TNF‑α‑mediated gluconeogenesis via targeting of PP4R1 in hepatocytes.

View Figures

View References

1	Shaw JE, Sicree RA and Zimmet PZ: Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. 87:4–14. 2010. View Article : Google Scholar : PubMed/NCBI
2	Gaggini M, Morelli M, Buzzigoli E, Defronzo RA and Gastaldelli A: Non-alcoholic fatty liver disease (NAFLD) and its connection with insulin resistance, dislipidemia, atherosclerosis and coronary heart disease. Nutrients. 5:1544–1560. 2013. View Article : Google Scholar : PubMed/NCBI
3	Puig-Domingo M and Pellitero S: New therapies for type 2 diabetes mellitus. Med Clin (Barc). 144:560–565. 2015.(In Spanish). View Article : Google Scholar : PubMed/NCBI
4	Erol A: Insulin resistance is an evolutionarily conserved physiological mechanism at the cellular level for protection against increased oxidative stress. Bioessays. 29:811–818. 2007. View Article : Google Scholar : PubMed/NCBI
5	Nordie RC, Foster JD and Lange AJ: Regulation of glucose production by the liver. Annu Rev Nutr. 19:379–406. 1999. View Article : Google Scholar : PubMed/NCBI
6	Leclercq IA, Da Silva Morais A, Schroyen B, Van Hul N and Geerts A: Insulin resistance in hepatocytes and sinusoidal liver cells: mechanisms and consequences. J Hepatol. 47:142–156. 2007. View Article : Google Scholar : PubMed/NCBI
7	Bugianesi E, McCullough AJ and Marchesini G: Insulin resistance: A metabolic pathway to chronic liver disease. Hepatology. 42:987–1000. 2005. View Article : Google Scholar : PubMed/NCBI
8	Lu M, Wan M, Leavens KF, Chu Q, Monks BR, Fernandez S, Ahima RS, Ueki K, Kahn CR and Birnbaum MJ: Insulin regulates liver metabolism in vivo in the abesence of hepatic akt and foxo1. Nat Med. 18:388–395. 2012. View Article : Google Scholar : PubMed/NCBI
9	Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, Adelmant G, Stafford J, Kahn CR, Granner DK, et al: Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature. 413:131–138. 2001. View Article : Google Scholar : PubMed/NCBI
10	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
11	Ono K: MicroRNA links obesity and impaired glucose metabolism. Cell Res. 21:864–866. 2011. View Article : Google Scholar : PubMed/NCBI
12	Zhao H, Huang X, Jiao J, Zhang H, Liu J, Qin W, Meng X, Shen T, Lin Y, Chu J and Li J: Protein phosphatase 4 (PP4) functions as a critical regulator in tumor necrosis factor (TNF)-α-induced hepatic insulin resistance. Sci Rep. 5:180932015. View Article : Google Scholar : PubMed/NCBI
13	Dou L, Wang S, Sun L, Huang X, Zhang Y, Shen T, Guo J, Man Y, Tang W and Li J: Mir-338-3p mediates Tnf-A-Induced hepatic insulin resistance by targeting PP4r1 to regulate PP4 expression. Cell Physiol Biochem. 41:2419–2431. 2017. View Article : Google Scholar : PubMed/NCBI
14	National Research Council (US) committee for the update of the Guide for the Care and Use of Labortory Animals: Guide for the care and use of laboratory animals. 8th. Washington (DC): Nation Academies Press; 2011
15	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Mehtods. 25:402–408. 2001.
16	Kim JH, Bachmann RA and Chen J: Interleukin-6 and insulin resistance. Vitam Horm. 80:613–633. 2009. View Article : Google Scholar : PubMed/NCBI
17	Fernandez-Valverde SL, Taft RJ and Mattick JS: MicroRNAs in β-cell biology, insulin resistance, diabetes and its complications. Diabetes. 60:1825–1831. 2011. View Article : Google Scholar : PubMed/NCBI
18	Guo J, Dou L, Meng X, Chen Z, Yang W, Fang W, Yang C, Huang X, Tang W, Yang J and Li J: Hepatic MiR-291b-3p mediated glucose metabolism by directly targeting p65 to upregulate PTEN expression. Sci Rep. 7:398992017. View Article : Google Scholar : PubMed/NCBI
19	Dou L, Zhao T, Wang L, Huang X, Jiao J, Gao D, Zhang H, Shen T, Man Y, Wang S and Li J: miR-200s contribute to interleukin-6 (IL-6)-induced insulin resistance in hepatocytes. J Biol Chem. 288:22596–22606. 2013. View Article : Google Scholar : PubMed/NCBI
20	Wang S, Wang L, Dou L, Guo J, Fang W, Li M, Meng X, Man Y, Shen T, Huang X and Li J: MicroRNA 152 regulates hepatic glycogenesis by targeting PTEN. FEBS J. 283:1935–1946. 2016. View Article : Google Scholar : PubMed/NCBI
21	Fang W, Guo J, Cao Y, Wang S, Pang C, Li M, Dou L, Man Y, Huang X, Shen T and Li J: MicroRNA-20a-5p contributes to hepatic glycogen synthesis through targeting p63 to regulate p53 and PTEN expression. J Cell Mol Med. 20:1467–1480. 2016. View Article : Google Scholar : PubMed/NCBI
22	Dou L, Meng X, Sui X, Wang S, Shen T, Huang X, Guo J, Fang W, Man Y, Xi J and Li J: MiR-19a regulates PTEN expression to mediate glycogen synthesis in hepatocytes. Sci Rep. 5:116022015. View Article : Google Scholar : PubMed/NCBI
23	Dou L, Wang S, Sui X, Meng X, Shen T, Huang X, Guo J, Fang W, Man Y, Xi J and Li J: MiR-301a mediates the effect of IL-6 on the AKT/GSK pathway and hepatic glycogenesis by regulating PTEN expression. Cell Physiol Biochem. 35:1413–1424. 2015. View Article : Google Scholar : PubMed/NCBI
24	Jacovetti C, Jimenez V, Ayuso E, Laybutt R, Peyot ML, Prentki M, Bosch F and Regazzi R: Contribution of intronic mir-338-3p and its hosting gene AATK to compensatory beta-cell mass expansion. Mol Endocrinol. 29:693–702. 2015. View Article : Google Scholar : PubMed/NCBI
25	Radzuk J and Pye S: Hepatic glucose uptake, gluconeogenesis and the regulation of glycogen synthesis. Diabetes Metab Res Rev. 17:250–272. 2001. View Article : Google Scholar : PubMed/NCBI
26	Oh KJ, Han HS, Kim MJ and Koo SH: Transcriptional regulators of hepatic gluconeogenesis. Arch Pharm Res. 36:189–200. 2013. View Article : Google Scholar : PubMed/NCBI
27	Kousteni S: FoxO1, the transcriptional chief of staff of energy metabolism. Bone. 50:437–443. 2012. View Article : Google Scholar : PubMed/NCBI
28	Puigserver P, Rhee J, Donovan J, Walkey CJ, Yoon JC, Oriente F, Kitamura Y, Altomonte J, Dong H, Accili D and Spiegelman BM: Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature. 423:550–555. 2003. View Article : Google Scholar : PubMed/NCBI