Suppressing the intestinal farnesoid X receptor/sphingomyelin phosphodiesterase 3 axis decreases atherosclerosis
Qing Wu, … , Frank J. Gonzalez, Changtao Jiang
Qing Wu, … , Frank J. Gonzalez, Changtao Jiang
Published May 3, 2021
Citation Information: J Clin Invest. 2021;131(9):e142865. https://doi.org/10.1172/JCI142865.
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Research Article Cardiology Vascular biology

Suppressing the intestinal farnesoid X receptor/sphingomyelin phosphodiesterase 3 axis decreases atherosclerosis

Abstract

Intestinal farnesoid X receptor (FXR) signaling is involved in the development of obesity, fatty liver disease, and type 2 diabetes. However, the role of intestinal FXR in atherosclerosis and its potential as a target for clinical treatment have not been explored. The serum levels of fibroblast growth factor 19 (FGF19), which is encoded by an FXR target gene, were much higher in patients with hypercholesterolemia than in control subjects and were positively related to circulating ceramide levels, indicating a link between intestinal FXR, ceramide metabolism, and atherosclerosis. Among ApoE–/– mice fed a high-cholesterol diet (HCD), intestinal FXR deficiency (in FxrΔIE ApoE–/– mice) or direct FXR inhibition (via treatment with the FXR antagonist glycoursodeoxycholic acid [GUDCA]) decreased atherosclerosis and reduced the levels of circulating ceramides and cholesterol. Sphingomyelin phosphodiesterase 3 (SMPD3), which is involved in ceramide synthesis in the intestine, was identified as an FXR target gene. SMPD3 overexpression or C16:0 ceramide supplementation eliminated the improvements in atherosclerosis in FxrΔIE ApoE–/– mice. Administration of GUDCA or GW4869, an SMPD3 inhibitor, elicited therapeutic effects on established atherosclerosis in ApoE–/– mice by decreasing circulating ceramide levels. This study identified an intestinal FXR/SMPD3 axis that is a potential target for atherosclerosis therapy.

Authors

Qing Wu, Lulu Sun, Xiaomin Hu, Xuemei Wang, Feng Xu, Bo Chen, Xianyi Liang, Jialin Xia, Pengcheng Wang, Daisuke Aibara, Shaofei Zhang, Guangyi Zeng, Chuyu Yun, Yu Yan, Yicheng Zhu, Michael Bustin, Shuyang Zhang, Frank J. Gonzalez, Changtao Jiang

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Figure 5

Forced expression of SMPD3 in the intestine negates FXR deficiency–mediated protection from atherosclerosis.

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Forced expression of SMPD3 in the intestine negates FXR deficiency–media...
Fxrfl/flApoE–/– and FxrΔIE ApoE–/– mice were surgically transfected with LV-GFP or LV-SMPD3 in the intestine, and then the mice were fed an HCD for 5 weeks (n = 8/group). (A and B) SMPD3 protein levels (A) and N-SMase activity (B) in the ileum. (C and D) Levels of ceramides in the ileum (C) and serum (D). (E and F) Representative images of aortas stained with Oil Red O (E) and quantification of the lesions (F). (G and H) Representative sections of left ventricular outflow tracts stained with Oil Red O (G) and the quantified lesion areas (H). (I and J) Immunofluorescence staining of atherosclerotic lesions for Mac-2 (I) and quantification of the positive areas (J). (K–M) Serum levels of the proinflammatory cytokines IL-1β (K), TNF-α (L), and MCP-1 (M). The data are presented as the mean ± SEM. One-way ANOVA with Tukey’s post hoc test (B, F, H, and J–M) and Kruskal-Wallis test with Dunn’s post hoc test (C and D): *P < 0.05, **P < 0.01 versus Fxrfl/fl ApoE–/– + LV-GFP and #P < 0.05, ##P < 0.01 versus FxrΔIE ApoE–/– + LV-GFP. Scale bars: 200 μm. The unedited Western blots from which the data in panel A were derived are shown in Supplemental Figure 10.