冬青苷 A 通过 HIF1α/SREBP-1 预防早期结肠癌变和重塑脂质代谢。
Ilexgenin A prevents early colonic carcinogenesis and reprogramed lipid metabolism through HIF1α/SREBP-1.
机构信息
State Key Laboratory of Natural Medicines, China Pharmaceutical University, 639 Longmian Road, Nanjing 211198, China.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, 639 Longmian Road, Nanjing 211198, China.
出版信息
Phytomedicine. 2019 Oct;63:153011. doi: 10.1016/j.phymed.2019.153011. Epub 2019 Jul 2.
BACKGROUND
Ilexgenin A (IA), the main bioactive compound from Ilex hainanensis Merr., has significant hypolipidemic activities. However, the effects of IA on colitis-associated colorectal cancer (CRC) and its mechanisms are still unknown.
PURPOSE
The study was designed to evaluate the effect of IA on CRC and explore its underlying mechanisms.
STUDY DESIGN
The effect of IA on colitis related CRC were evaluated in azoxymethane (AOM)/dextran sulfate sodium (DSS) mice and the underlying mechanisms were revealed by metabolomics, which were further validated in vivo and in vitro.
METHODS
The Balb/c mice were treated with AOM/DSS to induce CRC model and fed with normal diet with or without 0.02% IA. After the experimental period, samples of plasma were collected and analyzed by ultra-high-performance liquid chromatography/quadrupole time off light mass spectrometry (UHPLC-Q-TOF). Multivariate statistical tools were used to identify the changes of serum metabolites associated with CRC and responses to IA treatment. HT 29 and HCT 116 cells were stimulated by palmitate (PA) and cultured under hypoxia. Western blot, Q-PCR, and Immunofluorescence staining were performed to confirm the molecular pathway in vivo and in vitro.
RESULTS
Our results showed IA significantly inhibited the inflammatory colitis symptoms such as disease activity index score, shortening of colon tissues and the increase of inflammatory cytokines. In metabolomic study, 31 potential metabolites associated with CRC were identified and 24 of them were reversed by IA treatment. Most of biomarkers were associated with arachidonic acid metabolism, glycerophospholipid catabolism, and phospholipid metabolism, suggesting lipid metabolism might be involved in the beneficial effect of IA on CRC. Furthermore, we also found IA could decrease the expressions of SREBP-1 and its target gene in the colon tissues of AOM/DSS mice. It could down-regulate the triglyceride (TG) content and the expressions of HIF1α, SREBP-1, FASN, and ACC in HT 29 and HCT 116 cells. The inhibitory effect of IA on SREBP-1 was also attenuated by desferrioxamine (DFX), suggesting HIF1α is involved in the regulation of IA on SREBP-1.
CONCLUSION
IA prevents early colonic carcinogenesis in AOM/DSS mice and reprogramed lipid metabolism partly through HIF1α/SREBP-1.
背景
从冬青属植物海南冬青中提取的主要生物活性化合物 Ilexgenin A（IA）具有显著的降血脂活性。然而，IA 对结肠炎相关结直肠癌（CRC）的影响及其机制仍不清楚。
目的
本研究旨在评估 IA 对 CRC 的影响，并探讨其潜在机制。
研究设计
通过在氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎相关 CRC 模型中评估 IA 的作用，并通过代谢组学揭示其潜在机制，进一步在体内和体外进行验证。
方法
采用 AOM/DSS 处理 Balb/c 小鼠诱导 CRC 模型，并给予正常饮食加或不加 0.02%IA。实验结束后，采集血浆样本并通过超高效液相色谱/四极杆飞行时间质谱（UHPLC-Q-TOF）进行分析。采用多元统计工具鉴定与 CRC 相关的血清代谢物变化及对 IA 治疗的反应。用棕榈酸（PA）刺激 HT 29 和 HCT 116 细胞，并在低氧条件下培养。通过 Western blot、Q-PCR 和免疫荧光染色在体内和体外验证分子通路。
结果
结果显示，IA 显著抑制了炎症性结肠炎症状，如疾病活动指数评分、结肠组织缩短和炎症细胞因子的增加。在代谢组学研究中，鉴定出 31 种与 CRC 相关的潜在代谢物，其中 24 种代谢物被 IA 治疗逆转。大多数生物标志物与花生四烯酸代谢、甘油磷脂分解代谢和磷脂代谢有关，提示脂质代谢可能参与了 IA 对 CRC 的有益作用。此外，我们还发现 IA 可降低 AOM/DSS 小鼠结肠组织中 SREBP-1 及其靶基因的表达。IA 可降低 HT 29 和 HCT 116 细胞中 TG 含量及 HIF1α、SREBP-1、FASN 和 ACC 的表达。DFX 可减弱 IA 对 SREBP-1 的抑制作用，提示 HIF1α 参与了 IA 对 SREBP-1 的调控。
结论
IA 可预防 AOM/DSS 小鼠早期结直肠癌变，并通过 HIF1α/SREBP-1 部分重塑脂质代谢。
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