Resveratrol contributes to the inhibition of liver fibrosis by inducing autophagy via the microRNA‑20a‑mediated activation of the PTEN/PI3K/AKT signaling pathway

Zhu,Lili; Mou,Qiuju; Wang,Yinghui; Zhu,Zixin; Cheng,Mingliang

doi:10.3892/ijmm.2020.4748

Resveratrol contributes to the inhibition of liver fibrosis by inducing autophagy via the microRNA‑20a‑mediated activation of the PTEN/PI3K/AKT signaling pathway

Authors:
- Lili Zhu
- Qiuju Mou
- Yinghui Wang
- Zixin Zhu
- Mingliang Cheng
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Affiliations: Department of Blood Transfusion, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China, Department of Blood Transfusion, The Affiliated Baiyun Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China, Graduate School, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China, Department of Infectious Diseases, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
Published online on: October 9, 2020 https://doi.org/10.3892/ijmm.2020.4748
Pages: 2035-2046
Copyright: © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Liver fibrosis (LF) is a healing response to wounds resulting in liver injury that can cause liver failure or even cancer without functional prevention. Resveratrol (RSV) has been suggested to exert biological effects against various human diseases. MicroRNA‑20a (miRNA/miR‑20a) has been shown to promote disease progression. The present study aimed to assess the mechanisms through which RSV induces autophagy and activates the miR‑20a‑mediated phosphatase and tensin homolog (PTEN)/PI3K/AKT signaling pathway in LF. First, a rat model of carbon tetrachloride (CCL4)‑induced LF and a cell model of platelet‑derived growth factor (PDGF)‑BB‑stimulated HSC‑T6 cells were established for use in subsequent experiments. Subsequently, RSV at a range of concentrations was injected into the model rats with LF. Indicators related to liver injury, oxidative stress and fibrosis were determined in the rats with LF. The RSV‑treated HSC‑T6 cells were subjected to transfection with miR‑20a mimic and PTEN overexpression plasmid to assess the levels of liver injury and LF. A dual‑luciferase reporter gene assay was performed to verify the binding sites between PTEN and miR‑20a. RSV was found to alleviate LF in rats, and autophagy was enhanced in the rats with LF following RSV treatment. Furthermore, the activation of the PTEN/PI3K/AKT axis attenuated LF, which was reversed by transfection with miR‑20a mimic. RSV reversed the inhibitory effects of miR‑20a on PTEN expression, reducing miR‑20a expression and promoting PTEN, PI3K and p‑AKT protein expression, thus attenuating LF. On the whole, the present study demonstrates that RSV induces autophagy and activates the miR‑20a‑mediated PTEN/PI3K/AKT signaling pathway to attenuate LF. These findings may lead to the development of potential therapeutic strategies for LF.

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1	Schuppan D, Ashfaq-Khan M, Yang AT and Kim YO: Liver fibrosis: Direct antifibrotic agents and targeted therapies. Matrix Biol. 68-69:435–451. 2018. View Article : Google Scholar : PubMed/NCBI
2	Zoubek ME, Trautwein C and Strnad P: Reversal of liver fibrosis: From fiction to reality. Best Pract Res Clin Gastroenterol. 31:129–141. 2017. View Article : Google Scholar : PubMed/NCBI
3	Campana L and Iredale JP: Regression of liver fibrosis. Semin Liver Dis. 37:1–10. 2017. View Article : Google Scholar : PubMed/NCBI
4	Altamirano-Barrera A, Barranco-Fragoso B and Mendez- Sanchez N: Management strategies for liver fibrosis. Ann Hepatol. 16:48–56. 2017. View Article : Google Scholar : PubMed/NCBI
5	Poilil Surendran S, George Thomas R, Moon MJ and Jeong YY: Nanoparticles for the treatment of liver fibrosis. Int J Nanomedicine. 12:6997–7006. 2017. View Article : Google Scholar : PubMed/NCBI
6	Petitclerc L, Gilbert G, Nguyen BN and Tang A: Liver fibrosis quantification by magnetic resonance imaging. Top Magn Reson Imaging. 26:229–241. 2017. View Article : Google Scholar : PubMed/NCBI
7	Sun M and Kisseleva T: Reversibility of liver fibrosis. Clin Res Hepatol Gastroenterol. 39(Suppl 1): S60–S63. 2015. View Article : Google Scholar : PubMed/NCBI
8	Shi Y, Zhou J, Jiang B and Miao M: Resveratrol and inflamma-tory bowel disease. Ann N Y Acad Sci. 1403:38–47. 2017. View Article : Google Scholar : PubMed/NCBI
9	Hessin AF, Hegazy RR, Hassan AA, Yassin NZ and Kenawy SA: Resveratrol prevents liver fibrosis via two possible pathways: Modulation of alpha fetoprotein transcriptional levels and normalization of protein kinase C responses. Indian J Pharmacol. 49:282–289. 2017. View Article : Google Scholar
10	Liu C, Liao JZ and Li PY: Traditional Chinese herbal extracts inducing autophagy as a novel approach in therapy of nonalcoholic fatty liver disease. World J Gastroenterol. 23:1964–1973. 2017. View Article : Google Scholar : PubMed/NCBI
11	Li W, Zhang T, Guo L and Huang L: Regulation of PTEN expression by noncoding RNAs. J Exp Clin Cancer Res. 37:2232018. View Article : Google Scholar : PubMed/NCBI
12	Liang H, Wang X, Si C, Duan Y, Chen B, Liang H and Yang D: Downregulation of miR141 deactivates hepatic stellate cells by targeting the PTEN/AKT/mTOR pathway. Int J Mol Med. 46:406–414. 2020.PubMed/NCBI
13	Petersen DR, Saba LM, Sayin VI, Papagiannakopoulos T, Schmidt EE, Merrill GF, Orlicky DJ and Shearn CT: Elevated Nrf-2 responses are insufficient to mitigate protein carbonylation in hepatospecific PTEN deletion mice. PLoS One. 13:e01981392018. View Article : Google Scholar : PubMed/NCBI
14	Dong Z, Li S, Wang X, Si L, Ma R, Bao L and Bo A: lncRNA GAS5 restrains CCl₄-induced hepatic fibrosis by targeting miR-23a through the PTEN/PI3K/Akt signaling pathway. Am J Physiol Gastrointest Liver Physiol. 316:G539–G550. 2019. View Article : Google Scholar
15	Zhang DQ, Sun P, Jin Q, Li X, Zhang Y, Zhang YJ, Wu YL, Nan JX and Lian LH: Resveratrol regulates activated hepatic stellate cells by modulating NF-κB and the PI3K/Akt signaling pathway. J Food Sci. 81:H240–H245. 2016. View Article : Google Scholar
16	Chai R, Fu H, Zheng Z, Liu T, Ji S and Li G: Resveratrol inhibits proliferation and migration through SIRT1 mediated posttranslational modification of PI3K/AKT signaling in hepatocellular carcinoma cells. Mol Med Rep. 16:8037–8044. 2017. View Article : Google Scholar : PubMed/NCBI
17	Zhu Q, Luo M, Zhou C, Chen Z, Huang W, Huang J, Zhao S and Yu X: Effect of danusertib on cell cycle, apoptosis and autophagy of hepatocellular carcinoma HepG2 cells in vitro. Nan Fang Yi Ke Da Xue Xue Bao. 38:1476–1484. 2018.In Chinese.
18	Shrivastava S, Petrone J, Steele R, Lauer GM, Di Bisceglie AM and Ray RB: Up-regulation of circulating miR-20a is correlated with hepatitis C virus-mediated liver disease progression. Hepatology. 58:863–871. 2013. View Article : Google Scholar : PubMed/NCBI
19	Zhang Y, Zheng L, Ding Y, Li Q, Wang R, Liu T, Sun Q, Yang H, Peng S, Wang W and Chen L: MiR-20a induces cell radiore-sistance by activating the PTEN/PI3K/Akt signaling pathway in hepatocellular carcinoma. Int J Radiat Oncol Biol Phys. 92:1132–1140. 2015. View Article : Google Scholar : PubMed/NCBI
20	Dhar S, Kumar A, Rimando AM, Zhang X and Levenson AS: Resveratrol and pterostilbene epigenetically restore PTEN expression by targeting oncomiRs of the miR-17 family in pros-tate cancer. Oncotarget. 6:27214–27226. 2015. View Article : Google Scholar : PubMed/NCBI
21	Huang W, Li G, Qiu J, Gonzalez P and Challa P: Protective effects of resveratrol in experimental retinal detachment. PLoS One. 8:e757352013. View Article : Google Scholar : PubMed/NCBI
22	Saha L and Chakrabarti A: Understanding the anti-kindling role and its mechanism of Resveratrol in Pentylenetetrazole induced-kindling in a rat model. Pharmacol Biochem Behav. 120:57–64. 2014. View Article : Google Scholar : PubMed/NCBI
23	Zhan YY, Liang BQ, Li XY, Gu EM, Dai DP, Cai JP and Hu GX: The effect of resveratrol on pharmacokinetics of aripiprazole in vivo and in vitro. Xenobiotica. 46:439–444. 2016. View Article : Google Scholar
24	Zhang Y, Dong R, Yang Q, Zhang L, Li J and Zhao H: Resveratrol upregulates the gene and protein expressions of N-methyl-D-aspartate receptor 1 and protein kinase C in the hippocampus in Alzheimer's disease rats. Wei Sheng Yan Jiu. 48:269–278. 2019.In Chinese. PubMed/NCBI
25	Zatroch KK, Knight CG, Reimer JN and Pang DS: Refinement of intraperitoneal injection of sodium pentobarbital for euthanasia in laboratory rats (Rattus norvegicus). BMC Vet Res. 13:602017. View Article : Google Scholar : PubMed/NCBI
26	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
27	Brunt EM: Grading and staging the histopathological lesions of chronic hepatitis: The Knodell histology activity index and beyond. Hepatology. 31:241–246. 2000. View Article : Google Scholar
28	Zhang XW, Mi S, Li Z, Zhou JC, Xie J, Hua F, Li K, Cui B, Lv XX, Yu JJ and Hu ZW: Antagonism of Interleukin-17A ameliorates experimental hepatic fibrosis by restoring the IL-10/STAT3-suppressed autophagy in hepatocytes. Oncotarget. 8:9922–9934. 2017. View Article : Google Scholar : PubMed/NCBI
29	Zou H, Wang T, Yuan J, Sun J, Yuan Y, Gu J, Liu X, Bian J and Liu Z: Cadmium-induced cytotoxicity in mouse liver cells is associated with the disruption of autophagic flux via inhibiting the fusion of autophagosomes and lysosomes. Toxicol Lett. 321:32–43. 2020. View Article : Google Scholar
30	Niu X, Fu N, Du J, Wang R, Wang Y, Zhao S, Du H, Wang B, Zhang Y, Sun D and Nan Y: MiR-1273g-3p modulates activation and apoptosis of hepatic stellate cells by directly targeting PTEN in HCV-related liver fibrosis. FEBS Lett. 590:2709–2724. 2016. View Article : Google Scholar : PubMed/NCBI
31	Cheng Y, Tian Y, Xia J, Wu X, Yang Y, Li X, Huang C, Meng X, Ma T and Li J: The role of PTEN in regulation of hepatic macro-phages activation and function in progression and reversal of liver fibrosis. Toxicol Appl Pharmacol. 317:51–62. 2017. View Article : Google Scholar : PubMed/NCBI
32	Appourchaux K, Dokmak S, Resche-Rigon M, Treton X, Lapalus M, Gattolliat CH, Porchet E, Martinot-Peignoux M, Boyer N, Vidaud M, et al: MicroRNA-based diagnostic tools for advanced fibrosis and cirrhosis in patients with chronic hepatitis B and C. Sci Rep. 6:349352016. View Article : Google Scholar : PubMed/NCBI
33	Bae M, Park YK and Lee JY: Food components with antifibrotic activity and implications in prevention of liver disease. J Nutr Biochem. 55:1–11. 2018. View Article : Google Scholar
34	Abu-Amero KK, Kondkar AA and Chalam KV: Resveratrol and ophthalmic diseases. Nutrients. 8:2002016. View Article : Google Scholar : PubMed/NCBI
35	Faghihzadeh F, Hekmatdoost A and Adibi P: Resveratrol and liver: A systematic review. J Res Med Sci. 20:797–810. 2015. View Article : Google Scholar : PubMed/NCBI
36	Tang L, Yang F, Fang Z and Hu C: Resveratrol ameliorates alcoholic fatty liver by inducing autophagy. Am J Chin Med. 44:1207–1220. 2016. View Article : Google Scholar : PubMed/NCBI
37	Zhao X, Li R, Liu Y, Zhang X, Zhang M, Zeng Z, Wu L, Gao X, Lan T and Wang Y: Polydatin protects against carbon tetrachloride-induced liver fibrosis in mice. Arch Biochem Biophys. 629:1–7. 2017. View Article : Google Scholar : PubMed/NCBI
38	Ravanan P, Srikumar IF and Talwar P: Autophagy: The spotlight for cellular stress responses. Life Sci. 188:53–67. 2017. View Article : Google Scholar : PubMed/NCBI
39	Park D, Jeong H, Lee MN, Koh A, Kwon O, Yang YR, Noh J, Suh PG, Park H and Ryu SH: Resveratrol induces autophagy by directly inhibiting mTOR through ATP competition. Sci Rep. 6:217722016. View Article : Google Scholar : PubMed/NCBI
40	Ge MX, He HW, Shao RG and Liu H: Recent progression in the utilization of autophagy-regulating nature compound as anti-liver fibrosis agents. J Asian Nat Prod Res. 19:109–113. 2017. View Article : Google Scholar : PubMed/NCBI
41	Hopkins BD, Hodakoski C, Barrows D, Mense SM and Parsons RE: PTEN function: The long and the short of it. Trends Biochem Sci. 39:183–190. 2014. View Article : Google Scholar : PubMed/NCBI
42	He L, Gubbins J, Peng Z, Medina V, Fei F, Asahina K, Wang J, Kahn M, Rountree CB and Stiles BL: Activation of hepatic stellate cell in Pten null liver injury model. Fibrogenesis Tissue Repair. 9:82016. View Article : Google Scholar : PubMed/NCBI
43	Chen Q, Duan X, Fan H, Xu M, Tang Q, Zhang L, Shou Z, Liu X, Zuo D, Yang J, et al: Oxymatrine protects against DSS-induced colitis via inhibiting the PI3K/AKT signaling pathway. Int Immunopharmacol. 53:149–157. 2017. View Article : Google Scholar : PubMed/NCBI
44	Matsuda S, Kobayashi M and Kitagishi Y: Roles for PI3K/AKT/PTEN pathway in cell signaling of nonalcoholic fatty liver disease. ISRN Endocrinol. 2013:4724322013. View Article : Google Scholar : PubMed/NCBI
45	Tsai CY, Wu JCC, Fang C and Chang AYW: PTEN, a negative regulator of PI3K/Akt signaling, sustains brain stem cardiovascular regulation during mevinphos intoxication. Neuropharmacology. 123:175–185. 2017. View Article : Google Scholar : PubMed/NCBI
46	Babu KR and Muckenthaler MU: MiR-20a regulates expression of the iron exporter ferroportin in lung cancer. J Mol Med (Berl). 94:347–359. 2016. View Article : Google Scholar
47	Yuan J, Su Z, Gu W, Shen X, Zhao Q, Shi L, Jin C, Wang X, Cong H and Ju S: MiR-19b and miR-20a suppress apoptosis, promote proliferation and induce tumorigenicity of multiple myeloma cells by targeting PTEN. Cancer Biomark. 24:279–289. 2019. View Article : Google Scholar : PubMed/NCBI