Fluoride Exposure Suppresses Proliferation and Enhances Endoplasmic Reticulum Stress and Apoptosis Pathways in Hepatocytes by Downregulating Sirtuin-1

Overview

Journal Biomed Res Int

Publisher Wiley

Specialties Biomedical Engineering
Biotechnology
General Medicine

Date 2022 Sep 1

PMID 36046439

Authors

Yanlong Yu

Ling Li

Wenfeng Yu

Zhizhong Guan

Affiliations

Soon will be listed here.

Abstract

Objective: To explore the function and mechanism of Sirt-1 in fluorine-induced liver injury.

Method: Fluorosis rats were first established. The fluorine content, pathological structure, collagen fibers, and fibrosis in liver tissues were tested through the fluoride ion selective electrode method, H&E, Masson, and Sirius red staining; alanine aminotransferase (ALT), aspartate aminotransferase (AST), interleukin 18 (IL-18), and tumor necrosis factor- (TNF-) levels in rat serum were also analyzed using ELISA kits. Then, the fluorosis cell model was built, which was also alleviated with NaF, Sirt-1 siRNAs, or endoplasmic reticulum stress (ERS) alleviator (4-PBA). CCK-8 also assessed cell proliferation; RT-qPCR or Western blots detect sirtuin-1 (Sirt-1), protein kinase R- (PKR-) like endoplasmic reticulum kinase (PERK), and endoplasmic reticulum stress (ERS) and apoptosis-related protein levels in liver tissue.

Results: Our results uncovered that fluorine exposure could aggravate the pathological damage and fibrosis of rat liver tissues and increase indicators related to liver injury. And fluoride exposure also could downregulate Sirt-1 and upregulate ERS-related proteins (PERK, 78-kD glucose-regulated protein (GRP-78), and activating transcription factor 6 (ATF6)) and apoptosis-related protein (caspase-3 and C/EBP-homologous protein (CHOP)) in rat liver tissues. Besides, we proved that fluoride exposure could suppress proliferation and enhances ERS and apoptotic pathways in AML12 cells by downregulating Sirt-1. Moreover, we revealed that ERS alleviator (4-PBA) could induce proliferation and prevent ERS and apoptosis in fluorine-exposed AML12 cells.

Conclusions: We suggested that fluorine exposure can induce hepatocyte ERS and apoptosis through downregulation of Sirt-1.

Citing Articles

The role of sirtuin1 in liver injury: molecular mechanisms and novel therapeutic target.

Wang M, Zhao J, Chen J, Long T, Xu M, Luo T PeerJ. 2024; 12:e17094.

PMID: 38563003 PMC: 10984179. DOI: 10.7717/peerj.17094.

Retracted: Fluoride Exposure Suppresses Proliferation and Enhances Endoplasmic Reticulum Stress and Apoptosis Pathways in Hepatocytes by Downregulating Sirtuin-1.

International B Biomed Res Int. 2024; 2023:9763681.

PMID: 38188741 PMC: 10769702. DOI: 10.1155/2023/9763681.

SIRT1 as a Potential Therapeutic Target for Chronic Obstructive Pulmonary Disease.

Li S, Huang Q, He B Lung. 2023; 201(2):201-215.

PMID: 36790647 DOI: 10.1007/s00408-023-00607-9.

References

Yan H, Jihong Y, Feng Z, Xiaomei X, Xiaohan Z, Guangzhi W . Sirtuin 1-mediated inhibition of p66shc expression alleviates liver ischemia/reperfusion injury. Crit Care Med. 2014; 42(5):e373-81. DOI: 10.1097/CCM.0000000000000246. View

Nakamoto T, Rawls H . Fluoride Exposure in Early Life as the Possible Root Cause of Disease In Later Life. J Clin Pediatr Dent. 2018; 42(5):325-330. DOI: 10.17796/1053-4625-42.5.1. View

Zhang K, Lin L, Zhu Y, Zhang N, Zhou M, Li Y . Saikosaponin d Alleviates Liver Fibrosis by Negatively Regulating the ROS/NLRP3 Inflammasome Through Activating the ERβ Pathway. Front Pharmacol. 2022; 13:894981. PMC: 9174603. DOI: 10.3389/fphar.2022.894981. View

Qi Z, Chen L . Endoplasmic Reticulum Stress and Autophagy. Adv Exp Med Biol. 2019; 1206:167-177. DOI: 10.1007/978-981-15-0602-4_8. View

Li W, Dong S, Chen Q, Chen C, Dong Z . Selenium may suppress peripheral blood mononuclear cell apoptosis by modulating HSP70 and regulate levels of SIRT1 through reproductive hormone secretion and oxidant stress in women suffering fluorosis. Eur J Pharmacol. 2020; 878:173098. DOI: 10.1016/j.ejphar.2020.173098. View

Huo H, Wu H, Ma F, Li X, Liao J, Hu L . N-acetyl-L-cysteine ameliorates hepatocyte pyroptosis of dog type 1 diabetes mellitus via suppression of NLRP3/NF-κB pathway. Life Sci. 2022; 306:120802. DOI: 10.1016/j.lfs.2022.120802. View

Yang J, Wang M, Lu J, Yang K, Wang K, Liu M . Fluorine in the environment in an endemic fluorosis area in Southwest, China. Environ Res. 2020; 184:109300. DOI: 10.1016/j.envres.2020.109300. View

Zeng C, Hu X, He W, Wang Y, Li L, Xiong Y . Hypothermic machine perfusion ameliorates inflammation during ischemia‑reperfusion injury via sirtuin‑1‑mediated deacetylation of nuclear factor‑κB p65 in rat livers donated after circulatory death. Mol Med Rep. 2017; 16(6):8649-8656. PMC: 5779933. DOI: 10.3892/mmr.2017.7738. View

Chen X, Wang Y, Ji S, Sun X, Feng Q, Yu H . Hepatoprotective Efficacy and Interventional Mechanism of Qijia Rougan Decoction in Liver Fibrosis. Front Pharmacol. 2022; 13:911250. PMC: 9283647. DOI: 10.3389/fphar.2022.911250. View

10.

Trefts E, Gannon M, Wasserman D . The liver. Curr Biol. 2017; 27(21):R1147-R1151. PMC: 5897118. DOI: 10.1016/j.cub.2017.09.019. View

11.

Carreres L, Mercey-Ressejac M, Kurma K, Ghelfi J, Fournier C, Manches O . Chronic Intermittent Hypoxia Increases Cell Proliferation in Hepatocellular Carcinoma. Cells. 2022; 11(13). PMC: 9265377. DOI: 10.3390/cells11132051. View

12.

Qiao L, Liu X, He Y, Zhang J, Huang H, Bian W . Progress of Signaling Pathways, Stress Pathways and Epigenetics in the Pathogenesis of Skeletal Fluorosis. Int J Mol Sci. 2021; 22(21). PMC: 8584317. DOI: 10.3390/ijms222111932. View

13.

Ma L, Zhang R, Li D, Qiao T, Guo X . Fluoride regulates chondrocyte proliferation and autophagy via PI3K/AKT/mTOR signaling pathway. Chem Biol Interact. 2021; 349:109659. DOI: 10.1016/j.cbi.2021.109659. View

14.

Li X, Meng L, Wang F, Hu X, Yu Y . Sodium fluoride induces apoptosis and autophagy via the endoplasmic reticulum stress pathway in MC3T3-E1 osteoblastic cells. Mol Cell Biochem. 2018; 454(1-2):77-85. DOI: 10.1007/s11010-018-3454-1. View

15.

Lee S, Lee J, Lee H, Min K . Sirtuin signaling in cellular senescence and aging. BMB Rep. 2018; 52(1):24-34. PMC: 6386230. View

16.

Ramirez T, Li Y, Yin S, Xu M, Feng D, Zhou Z . Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression. J Hepatol. 2016; 66(3):601-609. PMC: 5316497. DOI: 10.1016/j.jhep.2016.11.004. View

17.

Luo X, Bai Y, He S, Sun S, Jiang X, Yang Z . Sirtuin 1 ameliorates defenestration in hepatic sinusoidal endothelial cells during liver fibrosis via inhibiting stress-induced premature senescence. Cell Prolif. 2021; 54(3):e12991. PMC: 7941223. DOI: 10.1111/cpr.12991. View

18.

Dusabimana T, Kim S, Kim H, Park S, Kim H . Nobiletin ameliorates hepatic ischemia and reperfusion injury through the activation of SIRT-1/FOXO3a-mediated autophagy and mitochondrial biogenesis. Exp Mol Med. 2019; 51(4):1-16. PMC: 6486618. DOI: 10.1038/s12276-019-0245-z. View

19.

Wang W, Sun W, Cheng Y, Xu Z, Cai L . Role of sirtuin-1 in diabetic nephropathy. J Mol Med (Berl). 2019; 97(3):291-309. PMC: 6394539. DOI: 10.1007/s00109-019-01743-7. View

20.

Dehnen S, Schafer L, Lectka T, Togni A . Fluorine: A Very Special Element and Its Very Special Impacts on Chemistry. J Org Chem. 2021; 86(23):16213-16219. DOI: 10.1021/acs.joc.1c02745. View