Ceramide-mediated gut dysbiosis enhances cholesterol esterification and promotes colorectal tumorigenesis in mice.
Ceramide-mediated gut dysbiosis enhances cholesterol esterification and promotes colorectal tumorigenesis in mice.
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神经酰胺介导的肠道菌群失调增强胆固醇酯化并促进小鼠结直肠肿瘤的发生
DOI：
10.1172/jci.insight.150607
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发表时间：
2022-02-08
期刊：
影响因子：
8
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Zhu Y;Gu L;Lin X;Zhang J;Tang Y;Zhou X;Lu B;Lin X;Liu C;Prochownik EV;Li Y
结直肠癌（Colorectal cancer，CRC）严重威胁着人类的健康和寿命。由于其发病机制尚不清楚，目前尚未建立有效的治疗策略。在这里，我们报告说，神经酰胺和甾醇O-酰基转移酶1（SOAT 1）在自发性和化学诱导的肠癌中发挥作用。我们首先发现，miRNA-148 a缺陷通过上调神经酰胺合成酶5（Cers 5）表达，从而促进神经酰胺合成，从而显著增加小鼠肠道生态失调。新产生的神经酰胺通过增加小鼠肠道生态失调进一步促进氧化偶氮甲烷/葡聚糖硫酸钠诱导的（AOM/DSS诱导的）和ApcMin/+自发性肠道肿瘤发生。同时，神经酰胺水平的增加与β-catenin活性的显著增强和结直肠肿瘤的发生以TLR 4依赖的方式相关。接下来，我们发现β-catenin与SOAT 1启动子直接结合，激活SOAT 1的转录表达，从而进一步诱导胆固醇酯化和结直肠肿瘤的发生。在患有CRC的人类患者中，也发现相同的CERS 5/TLR 4/β-连环蛋白/SOAT 1轴失调。最后，SOAT 1抑制剂（avasimibe）对AOM/DSS诱导的和ApcMin/+自发性肠癌都显示出显著的治疗效果。我们的研究阐明了神经酰胺通过增加肠道生态失调促进CRC的发展，进一步导致SOAT 1依赖性方式的胆固醇酯化增加。在未来的研究中，使用阿伐麦贝治疗以特异性降低胆固醇酯化可被视为有效CRC治疗的临床策略。
Colorectal cancer (CRC) severely threatens human health and life span. An effective therapeutic strategy has not been established because we do not clearly know its pathogenesis. Here, we report that ceramide and sterol O-acyltransferase 1 (SOAT1) have roles in both spontaneous and chemical-induced intestinal cancers. We first found that miRNA-148a deficiency dramatically increased mouse gut dysbiosis through upregulating ceramide synthase 5 (Cers5) expression, which promoted ceramide synthesis afterward. The newly generated ceramide further promoted both azoxymethane/dextran sodium sulfate–induced (AOM/DSS-induced) and ApcMin/+ spontaneous intestinal tumorigenesis via increasing mouse gut dysbiosis. Meanwhile, increased level of ceramide correlated with the significant enhancements of both β-catenin activity and colorectal tumorigenesis in a TLR4-dependent fashion. Next, we found a direct binding of β-catenin to SOAT1 promoter to activate transcriptional expression of SOAT1, which further induced cholesterol esterification and colorectal tumorigenesis. In human patients with CRC, the same CERS5/TLR4/β-catenin/SOAT1 axis was also found to be dysregulated. Finally, the SOAT1 inhibitor (avasimibe) showed significant levels of therapeutic effects on both AOM/DSS-induced and ApcMin/+ spontaneous intestinal cancer. Our study clarified that ceramide promoted CRC development through increasing gut dysbiosis, further resulting in the increase of cholesterol esterification in a SOAT1-dependent way. Treatment with avasimibe to specifically decrease cholesterol esterification could be considered as a clinical strategy for effective CRC therapy in a future study.
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影响因子：
3.7
作者：
Ayyagari, Vijayalakshmi N.;Wang, Xinjia;Brard, Laurent
通讯作者：
Brard, Laurent
DOI：
10.1002/cjp2.5
发表时间：
2015-01
期刊：
The journal of pathology. Clinical research
影响因子：
--
作者：
Fitzgerald S;Sheehan KM;Espina V;O'Grady A;Cummins R;Kenny D;Liotta L;O'Kennedy R;Kay EW;Kijanka GS
通讯作者：
Kijanka GS
影响因子：
3.9
作者：
Cleary, Joseph M.;Lipsky, Zachary W.;German, Guy K.
通讯作者：
German, Guy K.
影响因子：
8.8
作者：
Hu S;Peng L;Kwak YT;Tekippe EM;Pasare C;Malter JS;Hooper LV;Zaki MH
通讯作者：
Zaki MH
DOI：
10.1084/jem.20120239
发表时间：
2012-07-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Boulard O;Kirchberger S;Royston DJ;Maloy KJ;Powrie FM
通讯作者：
Powrie FM