Sirtuin1 and autophagy protect cells from fluoride-induced cell stress

Abstract

Sirtuin1 (SIRT1) is an (NAD+)-dependent deacetylase functioning in the regulation of metabolism, cell survival and organismal lifespan. Active SIRT1 regulates autophagy during cell stress, including calorie restriction, endoplasmic reticulum stress and oxidative stress. Previously, we reported that fluoride induces endoplasmic reticulum (ER) stress in ameloblasts responsible for enamel formation, suggesting that ER-stress plays a role in dental fluorosis. However, the molecular mechanism of how cells respond to fluoride-induced cell stress is unclear. Here, we demonstrate that fluoride activates SIRT1 and initiates autophagy to protect cells from fluoride exposure. Fluoride treatment of ameloblast-derived cells (LS8) significantly increased Sirt1 expression and induced SIRT1 phosphorylation resulting in the augmentation of SIRT1 deacetylase activity. To demonstrate that fluoride exposure initiates autophagy, we characterized the expression of autophagy related genes (Atg); Atg5, Atg7 and Atg8/LC3 and showed that both their transcript and protein levels were significantly increased following fluoride treatment. To confirm that SIRT1 plays a protective role in fluoride toxicity, we used resveratrol (RES) to augmented SIRT1 activity in fluoride treated LS8 cells. RES increased autophagy, inhibited apoptosis, and decreased fluoride cytotoxicity. Rats treated with fluoride (0, 50 and 100 ppm) in drinking water for 6 weeks had significantly elevated expression levels of Sirt1, Atg5, Atg7 and Atg8/LC3 in their maturation stage enamel organs. Increased protein levels of p-SIRT1, ATG5 and ATG8/LC3 were present in fluoride-treated rat maturation stage ameloblasts. Therefore, the SIRT1/autophagy pathway may play a critical role as a protective response to help prevent dental fluorosis.

Chronic Exposure to Bisphenol A Exacerbates Dental Fluorosis in Growing Rats

“…(46) Altogether, our results showed that the expression of three important groups of genes (EMPs, proteases, and SLCs) with major roles in amelogenesis was affected by exposure to both agents.…”

Effects of Fluoride on the Expression of Beclin1 and mTOR in Ameloblasts

“…The results reported in a previous study [Suzuki and Bartlett, 2014] led us to believe that autophagy is involved in the regulation of dental fluorosis as well as protein synthesis and enamel mineralization. However, further research was needed to illuminate the definite relationship between autophagy and apoptosis during dental fluorosis.…”

“…Previous investigations have shown that fluoride induces autophagy in the LS8 ameloblast cell line and in MC3T3-E1 osteoblastic cells [Suzuki and Bartlett, 2014;Wei et al, 2014]. However, few studies have investigated whether fluoride induces autophagy in the rat ameloblast cell line HAT-7.…”

ER stress-associated CTRC mutants decrease stimulated pancreatic zymogen secretion through SIRT2-mediated microtubule dysregulation

“…Treatment of ameloblast-derived LS8 cells with high doses of fluoride induces ER-stress and the expression of unfolded protein response transcription factors in a dose-dependent manner, as well as caspase-mediated apoptosis [24,25]. Remarkably, fluoride treatment increases SIRT1 expression and phosphorylation, resulting in an elevated deacetylase activity [25], as well as decreases extracellular secretion of the proteinases matrix metalloproteinase-20 and kallikrein-4 [24].…”