代谢功能障碍相关的脂肪肝疾病(MAFLD)涵盖了广泛的肝脏疾病,包括高血糖,肝脂肪变性,和胰岛素抵抗。胡椒长胺(PL),从PiperlongumL.的果实中提取的一种天然酰胺生物碱,在斑马鱼和肝损伤小鼠中表现出保肝作用。本研究旨在探讨PL对MAFLD的治疗潜力及其潜在机制。研究结果表明,PL可以有效对抗高脂饮食(HFD)诱导的MAFLD,并改善小鼠的代谢特征。此外,我们的结果表明,PL的抗MAFLD作用归因于抑制过度的肝糖异生,抑制从头脂肪生成,和减轻胰岛素抵抗。重要的是,结果表明,一方面,PL的降血糖作用与CREB调节的转录共激活因子(CRTC2)依赖性环AMP反应元件结合蛋白(CREB)磷酸化密切相关;另一方面,PL的降脂作用归因于减少固醇调节元件结合蛋白1c(Srebp-1c)的核定位.机械上,PL可以通过拮抗血栓烷A2受体(TP)/Ca2+信号减轻内质网应激诱导的胰岛素抵抗,TP受体是治疗MAFLD的潜在靶点。因此,我们的结果表明PL有效地改善了HFD诱导的MAFLD的主要标志,强调MAFLD的潜在治疗策略。
Metabolic dysfunction-associated fatty liver disease (MAFLD) encompasses a broad spectrum of hepatic disorders, including hyperglycemia, hepatic steatosis, and insulin resistance.
Piperlongumine (PL), a natural amide alkaloid extracted from the fruits of Piper longum L., exhibited hepatoprotective effects in zebrafish and liver injury mice. This study aimed to investigate the therapeutic potential of PL on MAFLD and its underlying mechanisms. The findings demonstrate that PL effectively combats MAFLD induced by a high-fat diet (HFD) and improves metabolic characteristics in mice. Additionally, our results suggest that the anti-MAFLD effect of PL is attributed to the suppression of excessive hepatic gluconeogenesis, inhibition of de novo lipogenesis, and alleviation of insulin resistance. Importantly, the results indicate that, on the one hand, the hypoglycemic effect of PL is closely associated with CREB-regulated transcriptional coactivators (CRTC2)-dependent cyclic AMP response element binding protein (CREB) phosphorylation; on the other hand, the lipid-lowering effect of PL is attributed to reducing the nuclear localization of sterol regulatory element-binding proteins 1c (Srebp-1c). Mechanistically, PL could alleviate insulin resistance induced by endoplasmic reticulum stress by antagonizing the thromboxane A2 receptor (TP)/Ca2+ signaling, and the TP receptor serves as the potential target for PL in the treatment of MAFLD. Therefore, our results suggested PL effectively improved the major hallmarks of MAFLD induced by HFD, highlighting a potential therapeutic strategy for MAFLD.