TMAO促进银屑病脂质代谢紊乱（英文）

TMAO promotes disorders of lipid metabolism in psoriasis

摘要

目的：银屑病与脂质代谢异常有关，但其潜在机制尚未阐明。本研究旨在探究三甲胺N-氧化物(trimethylamine N-oxide,TMAO)对银屑病脂质代谢紊乱的影响。方法：采用咪喹莫特(imiquimod,IMQ)诱导的银屑病模型小鼠来评估脂质代谢指标、TMAO水平及肝黄素单加氧酶3(flavin monooxygenase 3,FMO3)mRNA表达。收集健康人群和银屑病患者血液样本，测量TMAO水平和血脂含量。使用外源性TMAO腹腔注射、胆碱或3,3-二甲基-1-丁醇(3,3-dimethyl-1-butanol,DMB)饮食处理IMQ诱导的银屑病模型小鼠，阐明TMAO在银屑病模型小鼠脂质代谢失调中的作用。对小鼠的肝样本进行RNA测序(RNA sequencing,RNA-Seq)并探索TMAO调节的信号通路。结果：IMQ诱导的银屑病模型小鼠葡萄糖、胰岛素和脂质的水平异常。IMQ还导致小鼠肝中葡萄糖转运体2(glucose transporter 2,Glut2)和沉默信息调节因子1(silence information regulator 1,Sirt1)mRNA表达下调，以及葡萄糖转运体4(glucose transporter 4, Glut4)和过氧化物酶体增殖物激活受体γ(peroxisome proliferator-activated receptors gamma,PPARγ)mRNA表达上调。在银屑病患者和小鼠中均观察到血清TMAO水平升高。此外，银屑病小鼠肝FMO3 mRNA表达升高。银屑病患者血清TMAO水平与银屑病面积和严重指数(Psoriasis Area and Severity Index,PASI)评分及血清甘油三酯(triglyceride,TG)和总胆固醇(total cholesterol,TC)含量呈正相关。TMAO腹腔注射可导致IMQ诱导的银屑病小鼠脂质代谢紊乱。此外，富含胆碱的饮食可以加剧银屑病小鼠脂质异常和肝损伤，而DMB治疗可使其缓解。RNA-Seq分析表明TMAO上调小鼠肝中的microRNA-122(miR-122)表达，miR-122可能通过靶向gremlin 2(GREM2)抑制其表达，从而促进小鼠脂质代谢失调。结论：TMAO可能通过调节肝中miR-122/GREM2通路促进银屑病脂质代谢紊乱。

Abstract

Objective Psoriasis is associated with lipid metabolism disorders, but the underlying mechanisms remain unclear. This study aims to investigate the role of trimethylamine N-oxide (TMAO) in lipid metabolism dysregulation in psoriasis. Methods An imiquimod (IMQ)-induced psoriasis-like mouse model was used to assess lipid metabolism parameters, TMAO levels, and liver flavin monooxygenase 3 (FMO3) mRNA expression. Blood samples from healthy individuals and psoriatic patients were collected to measure serum TMAO levels and lipid profiles. To clarify the role of TMAO in the lipid metabolism disorder of mice with psoriasis model, exogenous TMAO, choline, or 3,3-dimethyl-1-butanol (DMB) were administered via intraperitoneal injections or diet in IMQ-treated mice. Liver tissues from the mouse models were subjected to RNA sequencing to identify TMAO-regulated signaling pathways. Results IMQ-induced psoriatic mice exhibited abnormal glucose, insulin, and lipid levels. IMQ treatment also downregulated the hepatic mRNA expression of glucose transporter 2 (Glut2) and silence information regulator 1 (Sirt1), while upregulating glucose transporter 4 (Glut4) and peroxisome proliferator-activated receptor gamma (PPARγ). Elevated serum TMAO levels were observed in both psoriatic patients and IMQ-treated mice. Additionally, liver FMO3 mRNA expression was increased in the psoriatic mouse model. In patients, TMAO levels positively correlated with Psoriasis Area and Severity Index (PASI) scores, serum triglyceride (TG), and total cholesterol (TC) levels. The intraperitoneal injection of TMAO exacerbated lipid dysregulation in IMQ-treated mice. A choline-rich diet further aggravated lipid abnormalities and liver injury in psoriatic mice, whereas DMB treatment alleviated these effects. RNA-Seq analysis demonstrated that TMAO upregulated hepatic microRNA-122 (miR-122), which may suppress the expression of gremlin 2 (GREM2), thus contributing to lipid metabolism disorder. Conclusion TMAO may promote lipid metabolism dysregulation in psoriasis by modulating the hepatic miR-122/GREM2 pathway.

关键词

银屑病 / 脂质代谢 / 三甲胺N-氧化物 / 微小核糖核酸-122 / gremlin 2

Key words

psoriasis / lipid metabolism / trimethylamine N-oxide / microRNA-122 / gremlin 2