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Abstract

This article has been Retracted.

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-a (TNF-a) 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.

*Original article online at https://www.hindawi.com/journals/bmri/2022/7380324/

Excerpt:

1. Introduction

Fluorine exists in the environment in the form of fluoride [1]. And fluorine is a vital trace element present in humans and animals, mainly in bones and teeth [2, 3]. While long-term exposure to fluoride in the air, food, and water can lead to fluorosis, it can also cause dental fluorosis and fluorosis bone disease [4]. It has also been confirmed that chronic fluorosis can result in extensive pathological damage to the body [5]. Excessive intake of fluorine will cause morphological, functional, and metabolic changes in various organs, exposing soft tissues such as the liver, nerves, kidneys, blood vessels, and muscles to fluorine damage [6, 7]. The liver is the largest tissue organ in the body and can be involved in metabolism and blood production. Besides, the liver is the main organ for removing toxic substances from living organisms [8]. Long-term chronic fluoride exposure can lead to the accumulation of large amounts of fluoride in the liver, destroying its tissue morphology and affecting its normal physiological functions [9]. Several studies have indicated that sodium fluoride (NaF) can induce mitochondrial damage and promote hepatotoxicity and cellular damage [10, 11]. However, the mechanism of NaF-induced hepatotoxicity has not been clearly elucidated.

The endoplasmic reticulum (ER) is the site of protein synthesis, folding, and quality control [12]. During stressful conditions, unfolded and misfolded proteins can accumulate in the ER lumen, eventually causing ER stress (ERS) [13]. Research showed that ERS is associated with liver injury, and ERS-associated apoptosis is present throughout the process of liver injury [14]. Therefore, regulating ERS-associated apoptosis is very important to prevent liver injury.

Histone deacetylase (HDAC) can modify chromatin structure and regulate transcription factor activity [15]. And sirtuin-1 (Sirt-1) is a class III HDAC and can regulate biological processes including cellular metabolism, gene transcription, immune response, and glucose homeostasis through multiple deacetylation factors [16]. Sirt-1 has been reported to be associated with cell growth, apoptosis, senescence, autophagy, and other activities, which plays a key role in several diseases, such as neurodegenerative diseases, metabolic diseases, and cancer [17–19]. Several researchers have also confirmed that Sirt-1 is relevant to liver injury [20–22]. Besides, Sirt-1 also can exert a protective role against liver injury by suppressing ERS [23]. Recent study also revealed that Sirt-1 can weaken ERS by inhibiting the protein kinase R- (PKR-) like endoplasmic reticulum kinase- (PERK-) eIF2a-activating transcription factor 4 (ATF4) pathway, ultimately reducing ERS-induced apoptosis [24]. However, whether Sirt-1 can be involved in fluorine exposure-induced ERS in hepatocytes is not fully understood.

4. Discussion

Fluoride is widely present in the natural environment [33]. And long-term fluorine exposure can have certain toxic effects on the organism and cause significant hepatic pathological damage [34]. Currently, a study demonstrated that fluoride exposure could cause liver damage by the mitochondrial apoptosis pathway [9]. AST and ALT are the earliest and most sensitive indicators of the appearance of liver injury [35]. When liver tissue is necrotic or damaged, ALT and AST escape from hepatocytes and enter the bloodstream, significantly increasing serum ALT and AST activity [36]. Therefore, the increase of ALT and AST activity in serum reflects the degree of hepatocellular injury to a certain extent. In our study, we further proved that NaF treatment could induce necrosis and nuclear sequestration in hepatocytes and reduce intracellular organelles and swollen mitochondria in liver tissues of rats. Meanwhile, NaF also could elevate the levels of liver injury-related indicators (ALT and AST) and inflammatory indicators (IL-18, TNF-a) in rat serum. These results suggested that fluorine could induce liver injury in a dose-dependent manner.

Hepatic fibrosis (HF) is a repair response of the liver in response to chronic injury [37]. HF is also an intermediate stage in the progression of chronic liver disease to cirrhosis, which is a key stage in reversing the disease [38]. Late-stage HF may progress to irreversible cirrhosis [39]. And cirrhosis may further cause ascites, splenomegaly, formation of collateral circulation, upper gastrointestinal bleeding, and even death [40]. Our data further verified that fluorine exposure also could accelerate liver fibrosis in rats. Therefore, fluorine exposure can enhance liver injury and induce liver fibrosis.

Fluorosis is mainly associated with oxidative stress, hormonal regulation, and apoptosis [41]. Research showed that signaling pathways and related factors are relevant to fluorosis [42, 43]. To further explore the underlying mechanisms of fluorosis-induced liver injury, we investigated the effects of fluorine on hepatocyte ERS and apoptotic pathways. Apoptosis, a form of programmed cell death, can be induced by different toxic stimuli [44]. The literature reported that excess NaF could cause apoptosis in different cell types, including osteoblasts and human embryonic stem cells [45, 46]. And ERS is one of the key pathways of fluorine-induced apoptosis [47]. ERS acts as a cellular self-protection mechanism and normally has a role in protecting cells from damage. Adverse environments, such as oxidative stress and toxic stimuli, can accumulate unfolded and misfolded proteins in the ER, which can activate the unfolded protein response (UPR) [48]. UPR can maintain the balance of ER quantity and normal function in the body during ERS. Under stress, GRP78 can activate ERS through PERK, ATF6, and IRE1 [49]. While excessive ERS instead can activate ERS-associated apoptotic proteins such as CHOP, it can eventually trigger apoptosis [50]. In vivo study also showed that high fluorine concentrations can induce ERS and apoptosis in osteoblasts [51]. Our study further verified that fluoride exposure could upregulate ERS-and apoptosis-related proteins in liver tissues and AML12 cells. Thus, fluoride exposure could induce ERS and apoptosis in hepatic cells. Meanwhile, we discovered that ERS alleviator (4-PBA) could induce proliferation and inhibit ERS and apoptosis in fluorine-exposed AML12 cells, suggesting that fluorine exposure to hepatocyte ERS is critical.

More importantly, our data showed that fluoride exposure could prominently downregulate Sirt-1 in liver tissues and AML12 cells. Sirt-1 is a deacetylase that can regulate biological metabolism through deacetylation [52]. Besides, Sirt-1 has been reported to play key regulatory roles in physiological processes such as apoptosis, differentiation, oxidative stress, senescence, signaling, transcriptional regulation, and metabolic regulation through the regulation of histones, NF-kB, FOXO, and p53 [53, 54]. In recent years, studies confirmed that Sirt-1 is essential in liver-related diseases, such as liver transplantation [55], liver ischemia/reperfusion injury [56], liver fibrosis [57], fatty liver [58], alcoholic liver injury, and fibrosis [59]. At the same time, the role and mechanism of Sirt-1 in liver injury induced by fluoride exposure are unclear. Our results further indicated that Sirt-1 knockdown could further enhance the induction of ERS and apoptosis mediated by fluorine exposure in AML12 cells.

In our study, we first constructed fluorosis rat and cell models using NaF and clarified the influences of fluorine exposure on liver injury and fibrosis in rats. Besides, we explored the impacts of fluorine exposure on ERS- and apoptosis-related proteins in fluorosis rats and cells. Moreover, we further verified the action of Sirt-1 silencing and ERS alleviator (4-PBA) in fluorine-exposed rat liver tissues in vivo and AML12 cells in vitro. Therefore, the investigation of the protective mechanism of SIRT-1 against fluoride exposure-induced liver injury may provide a laboratory basis for the future clinical mitigation of fluorosis.

5. Conclusion

We demonstrated that fluorine exposure could induce hepatocyte injury through modulation of ERS and apoptotic pathways. Besides, Sirt-1 knockdown could further enhance the ERS and apoptotic processes in hepatocytes induced by fluoride exposure and enhance the toxic effects of NaF (Figure 6).

Figure 6 
Schematic representation of the process that SIRT-1 against fluoride exposure-induced liver injury.

Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding authors on reasonable request.

Conflicts of Interest

The authors declare no competing interests.

Authors’ Contributions

Yanlong Yu and Ling Li contributed equally to this work.

Acknowledgments

This work was supported by the Special Funds for the Central Government to Guide Local Science and Technology Development (grant no. QKZYD(2019)4008).

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Copyright © 2022 Yanlong Yu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Original study online at https://www.hindawi.com/journals/bmri/2022/7380324/
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