Key Laboratory of Tropical and Subtropical Fishery Resource Application and Cultivation, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, China.
Front Endocrinol (Lausanne). 2022 Jul 28;13:950985. doi: 10.3389/fendo.2022.950985. eCollection 2022.
The pregnane X receptor (PXR) is a master xenobiotic-sensing receptor in response to toxic byproducts, as well as a key regulator in intermediary lipid metabolism. Therefore, the present study was conducted to investigate the potential role of PXR in mediating the lipid dysregulation and xenobiotic responses under Cu-induced stress in largemouth bass (). Four groups of largemouth bass (52.66 ± 0.03 g) were treated with control, Cu waterborne (9.44 μmol/L), Cu+RIF (Rifampicin, 100 mg/kg, PXR activator), and Cu+KET (Ketoconazole, 20 mg/kg, PXR inhibitor) for 48 h. Results showed that Cu exposure significantly elevated the plasma stress indicators and triggered antioxidant systems to counteract Cu-induced oxidative stress. Acute Cu exposure caused liver steatosis, as indicated by the significantly higher levels of plasma triglycerides (TG), lipid droplets, and mRNA levels of lipogenesis genes in the liver. Liver injuries were detected, as shown by hepatocyte vacuolization and severe apoptotic signals after Cu exposure. Importantly, Cu exposure significantly stimulated mRNA levels of PXR, suggesting the response of this regulator in the xenobiotic response. The pharmacological intervention of PXR by the agonist and antagonist significantly altered hepatic mRNA levels of PXR, implying that RIF and KET were effective agents of PXR in largemouth bass. Administration of RIF significantly exacerbated liver steatosis, and such alterations were dependent on the regulations on and rather than signaling, which suggested that PXR-PPARγ might be another pathway for Cu-induced lipid deposition in fish. Whereas, KET administration showed reverse effects on lipid metabolism as indicated by the lower hepatic TG levels, suppressed mRNA levels of and . Activation of PXR stimulated autophagy and inhibited apoptosis, leading to lower hepatic vacuolization; while inhibition of PXR showed higher apoptotic signals, inhibition of autophagic genes and stimulation of apoptotic genes. Taken together, PXR played a cytoprotective role in Cu-induced hepatotoxicity through regulations on autophagy and apoptosis. Overall, our data has demonstrated for the first time on the dual roles of PXR as a co-regulator in mediating xenobiotic responses and lipid metabolism in fish, which implying the potential of PXR as a therapy target for xenobiotics-induced lipid dysregulation and hepatotoxicity.
孕激素相关受体（PXR）是一种对毒性副产物以及中间脂质代谢的关键调节因子作出反应的外来物质感应受体。因此，本研究旨在探讨 PXR 在介导铜胁迫下大口黑鲈（）中脂质失调和外来物质反应中的潜在作用。将 4 组大口黑鲈（52.66 ± 0.03 g）分别用对照、铜水（9.44 μmol/L）、铜+RIF（利福平，PXR 激活剂，100 mg/kg）和铜+KET（酮康唑，PXR 抑制剂，20 mg/kg）处理 48 h。结果表明，铜暴露显著提高了血浆应激指标，并启动了抗氧化系统来抵抗铜诱导的氧化应激。急性铜暴露导致肝脏脂肪变性，表现为血浆甘油三酯（TG）水平显著升高，肝脏脂质滴增多，以及肝脏中脂肪生成基因的 mRNA 水平升高。铜暴露后检测到肝损伤，表现为肝细胞空泡化和严重的凋亡信号。重要的是，铜暴露显著刺激了 PXR 的 mRNA 水平，表明该调节剂对外来物质反应作出了响应。激动剂和拮抗剂对 PXR 的药理学干预显著改变了肝脏 PXR 的 mRNA 水平，表明 RIF 和 KET 是大口黑鲈中 PXR 的有效药物。RIF 的给药显著加剧了肝脏脂肪变性，这种改变依赖于和而不是信号通路的调节，这表明 PXR-PPARγ 可能是鱼类铜诱导脂质沉积的另一种途径。相反，KET 的给药对脂质代谢表现出相反的作用，表现为肝脏 TG 水平降低，和的 mRNA 水平受到抑制。PXR 的激活刺激自噬并抑制凋亡，导致肝脏空泡化减少；而 PXR 的抑制显示出更高的凋亡信号，抑制自噬基因并刺激凋亡基因。总之，PXR 通过调节自噬和凋亡在铜诱导的肝毒性中发挥细胞保护作用。总的来说，我们的数据首次证明了 PXR 作为一种调节因子在介导鱼类外来物质反应和脂质代谢中的双重作用，这表明 PXR 作为治疗外来物质诱导的脂质失调和肝毒性的潜在靶点。
