Methylparaben (MP), a preservative widely used in daily supplies, exists in both the environment and the human body. However, the potential health risks posed by MP remain unclear. This study aimed to unravel the mechanisms by which MP disrupts glucose and lipid homeostasis. For this, we administered MP to mice and observed changes in glucose and lipid metabolism. MP exposure led to hyperglycemia, hyperlipidemia, visceral organ injury, and hepatic lipid accumulation. RNA sequencing results from mice livers indicated a close association between MP exposure and endoplasmic reticulum (ER) stress, inflammatory response, and glucose and lipid homeostasis. Western blotting and quantitative reverse transcription–polymerase chain reaction revealed that MP activated ER stress, particularly the inositol-requiring enzyme 1 (IRE1)/X-box binding protein 1 (XBP1) pathway, which further promoted the activation of the nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. The activation of these pathways phosphorylated insulin receptor substrate-1 (IRS1) (ser 307), resulting in decreased phosphorylation of protein kinase B (Akt) (ser 473), leading to insulin resistance. Additionally, MP exposure promoted lipogenesis through ER stress. To explore potential remedies, we administered the ER stress inhibitor 4-phenylbutyric acid (4-PBA) and the IRE1α-XBP1 pathway inhibitor toyocamycin to mice, both of which protected against metabolic disorders and organ injury caused by MP. These findings suggest that MP induces disruptions in glucose and lipid metabolism through ER stress, primarily through the IRE1α-XBP1 pathway.

对羟基苯甲酸甲酯（MP）是一种广泛用于日常用品的防腐剂，存在于环境和人体中。然而，MP 带来的潜在健康风险仍不清楚。本研究旨在揭示 MP 破坏葡萄糖和脂质稳态的机制。为此，我们给小鼠注射 MP 并观察葡萄糖和脂质代谢的变化。 MP暴露导致高血糖、高脂血症、内脏器官损伤和肝脏脂质堆积。小鼠肝脏的 RNA 测序结果表明 MP 暴露与内质网 (ER) 应激、炎症反应以及葡萄糖和脂质稳态之间存在密切关联。蛋白质印迹和定量逆转录聚合酶链反应表明，MP 激活 ER 应激，特别是肌醇需求酶 1 (IRE1)/X-box 结合蛋白 1 (XBP1) 途径，进一步促进核因子 kappa 的激活B (NF-κB) 和丝裂原激活蛋白激酶 (MAPK) 途径。这些途径的激活会磷酸化胰岛素受体底物 1 (IRS1)（第 307 位序列），导致蛋白激酶 B (Akt)（第 473 位序列）的磷酸化降低，从而导致胰岛素抵抗。此外，MP 暴露通过 ER 应激促进脂肪生成。为了探索潜在的补救措施，我们给小鼠注射了 ER 应激抑制剂 4-苯基丁酸 (4-PBA) 和 IRE1α-XBP1 通路抑制剂丰加霉素，这两种药物都可以预防 MP 引起的代谢紊乱和器官损伤。这些发现表明 MP 通过 ER 应激（主要是通过 IRE1α-XBP1 途径）诱导葡萄糖和脂质代谢的破坏。