Guo Yuchao, Mao Houlin, Gong Danni, Zhang Nuo, Gu Dandan, Okeke Emmanuel Sunday, Feng Weiwei, Chen Yao, Mao Guanghua, Zhao Ting, Yang Liuqing
School of Chemistry and Chemical Engineering, Jiangsu University, Xuefu Rd. 301, Zhenjiang 212013, China.
School of the Environment, Jiangsu University, Xuefu Rd. 301, Zhenjiang, Jiangsu 212013, China; Department of Biochemistry, Faculty of Biological Science & Natural Science Unit, School of General Studies, University of Nigeria, Nsukka, Enugu 410001, Nigeria.
Toxicology. 2024 May;504:153800. doi: 10.1016/j.tox.2024.153800. Epub 2024 Apr 9.
Acrylamide (ACR) is an endogenous food contaminant, high levels of ACR have been detected in a large number of foods, causing widespread concern. Since different organism states respond differently to the toxic effects of pollutants, this study establishes an insulin-resistant BRL cell model to explore the differential susceptibility of BRL cells with/without insulin resistance in response to acrylamide-exposure (0.0002, 0.02, or 1 mM) toxicity effects and its mechanism. The results showed that ACR exposure decreased glucose uptake and increased intracellular lipid levels by promoting the expression of fatty acid synthesis, transport, and gluconeogenesis genes and inhibiting the expression of fatty acid metabolism genes, thereby further exacerbating disorders of gluconeogenesis and lipid metabolism in insulin-resistant BRL cells. Simultaneously, its exposure also exacerbated BRL cells with/without insulin-resistant damage. Meanwhile, insulin resistance significantly raised susceptibility to BRL cell response to ACR-induced toxicity. Furthermore, ACR exposure further activated the endoplasmic reticulum stress (ERS) signaling pathway (promoting phosphorylation of PERK, eIF-2α, and IRE-1α) and the apoptosis signaling pathway (activating Caspase-3 and increasing the Bax/Bcl-2 ratio) in BRL cells with insulin-resistant, which were also attenuated after ROS scavenging or ERS signaling pathway blockade. Overall results suggested that ACR evokes a severer toxicity effect on BRL cells with insulin resistance through the overactivation of the ERS signaling pathway.
丙烯酰胺（ACR）是一种内源性食品污染物，大量食品中已检测到高含量的ACR，引起了广泛关注。由于不同机体状态对污染物毒性作用的反应不同，本研究建立了胰岛素抵抗的BRL细胞模型，以探讨有/无胰岛素抵抗的BRL细胞对丙烯酰胺暴露（0.0002、0.02或1 mM）毒性作用的差异敏感性及其机制。结果表明，ACR暴露通过促进脂肪酸合成、转运和糖异生基因的表达并抑制脂肪酸代谢基因的表达，降低了葡萄糖摄取并增加了细胞内脂质水平，从而进一步加剧了胰岛素抵抗的BRL细胞中糖异生和脂质代谢的紊乱。同时，其暴露也加剧了有/无胰岛素抵抗的BRL细胞损伤。此外，胰岛素抵抗显著提高了BRL细胞对ACR诱导毒性反应的敏感性。此外，ACR暴露进一步激活了胰岛素抵抗的BRL细胞中的内质网应激（ERS）信号通路（促进PERK、eIF-2α和IRE-1α的磷酸化）和凋亡信号通路（激活Caspase-3并增加Bax/Bcl-2比值），在清除ROS或阻断ERS信号通路后这些也减弱了。总体结果表明，ACR通过过度激活ERS信号通路对有胰岛素抵抗的BRL细胞产生更严重的毒性作用。
