Ceramide-mediated gut dysbiosis enhances cholesterol esterification and promotes colorectal tumorigenesis in mice
Yahui Zhu, Li Gu, Xi Lin, Jinmiao Zhang, Yi Tang, Xinyi Zhou, Bingjun Lu, Xingrong Lin, Cheng Liu, Edward V. Prochownik, Youjun Li
Yahui Zhu, Li Gu, Xi Lin, Jinmiao Zhang, Yi Tang, Xinyi Zhou, Bingjun Lu, Xingrong Lin, Cheng Liu, Edward V. Prochownik, Youjun Li
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Research Article Gastroenterology Metabolism

Ceramide-mediated gut dysbiosis enhances cholesterol esterification and promotes colorectal tumorigenesis in mice

Abstract

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.

Authors

Yahui Zhu, Li Gu, Xi Lin, Jinmiao Zhang, Yi Tang, Xinyi Zhou, Bingjun Lu, Xingrong Lin, Cheng Liu, Edward V. Prochownik, Youjun Li

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Figure 1

Depletion of miR-148a increases gut dysbiosis to enhance colorectal tumorigenesis.

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Depletion of miR-148a increases gut dysbiosis to enhance colorectal tumo...
(A) Representative images of colon tumors from WT and miR-148a–/– mice under separately housed and cohoused situations. (B) Colon tumor numbers (left) and average tumor volumes (right) from A (n = 10–12/group). (C) The relative levels of indicated gut microbiota of mice from A after quantitative PCR (qPCR) analysis (n = 3/group). (A–C) Separately housed or cohoused WT and miR-148a–/– mice were injected with AOM on day 0 and were treated with 3 rounds of 2.5% DSS in drinking water from day 0 to day 7 for 7 days followed by regular drinking water. (D) Representative images of colon tumors from WT and miR-148a–/– mice treated with control (Ctrl) or antibiotics mix. (E–G) Colon tumor numbers (E), tumor sizes, (F) and average tumor volumes (G) from D (n = 10–13/group). (H) qPCR analyses on bacterial 16s rDNA of gut microbiota from D (n = 3/group). (Data were presented as mean ± SEM in B, and E–G.) *P < 0.05, **P < 0.01, ****P < 0.0001. Statistical significance was calculated by using 1-way ANOVA (B) or 2-tailed unpaired t test (E, F, and G).