Endoplasmic reticulum stress-mediated autophagy activation attenuates fumonisin B1 induced hepatotoxicity in vitro and in vivo. (December 2017)

• Record Type: Journal Article
• Authors: Singh, Mahendra Pal; Kang, Sun Chul
• Is Part Of: Food and chemical toxicology. Volume 110(2017)
• Page Start: 371
• Page End: 382
• Publication Date: 2017-12
• Subjects: Autophagy -- Endoplasmic reticulum stress -- Fumonisin B1 -- Hepatotoxicity -- Reactive oxygen species; FB1 fumonisin B1 -- ALT alanine aminotransferase -- AST aspartate aminotransferase -- ALP alkaline phosphatase -- PKC protein kinase C -- AMPK AMP-dependent protein kinase -- ATG AuTophaGy-related gene -- Cyt c cytochrome c -- GR glutathione reductase -- ROS reactive oxygen species -- ER endoplasmic reticulum -- NAC N-acetyl-l-cysteine -- 3-MA 3-methyladenine -- Rap rapamycin; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2017.10.054
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: Although pathological characteristics of fumonisin B1 are known to induce hepatic injury over prolonged periods, the cellular defense mechanisms against the detrimental effects of FB1 are still unknown. The underlying mechanisms of FB1 toxicity are thought to be related with the inhibition of ceramide synthase, causing an accumulation of sphingoid bases, which in turn cause development of oxidative stress. Herein, we investigated whether autophagy, a cellular defense mechanism, protects liver cells from FB1 exposure. To accomplish this, we utilized HepG2 cells and a mouse model to study the effects of FB1 in the autophagy pathway. FB1 was capable of inducing autophagy via the generation of ROS, induction of endoplasmic reticulum stress, phosphorylation of JNK, suppression of mTOR and activation of LC3I/II in HepG2 cells and mice livers. Treatment of HepG2 cells with the ROS scavenger N -acetyl-l -cysteine alleviated ER stress stimulation and induced HepG2 cell death. Moreover, suppression of autophagy with 3-Methyladenine enhanced HepG2 cells apoptosis. Concurrently, four consecutive days exposure of mice livers to FB1 altered the levels of sphingoid bases, hepatic enzymes and induced histopathological changes. Moreover, the expression levels of major ER stress and autophagy-related markers such as PERK, IRE1-α, and LC3I/II also increased. Autophagy activation protected HepG2 cells and mice livers from the lethal effects of FB1. Hence, these findings specify that, the compounds that modify autophagy might be useful therapeutic agents for treatment of patients with FB1 induced liver ailments. Highlights: HepG2 cells and mice liver exposed to FB1 induced oxidative stress mediated cellular damage. Time dependent exposure of FB1 altered liver histology and the levels of hepatic enzymes in mice. ROS mediated signaling helps in the activation of ER stress mediated autophagy in vitro and in vivo. Cellular autophagy induction recovered hepatocytes from FB1 toxicity by long term exposure.