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 7

Oral GUDCA or GW4869 administration postpones progression of established atherosclerotic lesions.

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Oral GUDCA or GW4869 administration postpones progression of established...
ApoE–/– mice were fed an HCD for 5 weeks, and vehicle or GUDCA was administered by gavage under chow diet feeding for another 3 weeks (n = 8/group). (A and B) Representative images (A) and quantification (B) of aortic plaque areas. (C and D) Representative Oil Red O–stained sections of left ventricular outflow tracts (C) and quantification of the plaque areas (D). (E and F) Representative images of left ventricular outflow tract sections stained for Mac-2 (E) and statistical analysis of the Mac-2–positive areas (F). (G) Serum IL-1β levels. (H and I) Levels of ceramides in the ileum (H) and serum (I). ApoE–/– mice were fed an HCD for 5 weeks and treated daily with GW4869 by gavage under chow diet feeding for another 3 weeks (n = 8/group). (J and K) Representative images (J) and quantification (K) of the aortic plaque areas. (L and M) Representative Oil Red O–stained cross sections of aortic roots (L) and quantification of the lesion areas (M). (N and O) Immunofluorescence staining for Mac-2 (N) and statistical analysis of the Mac-2–positive areas (O). (P) Serum IL-1β levels. (Q and R) Levels of ceramides in the ileum (Q) and serum (R). The data are presented as the mean ± SEM. Two-tailed Student’s t test (B, D, F, G, K, M, O, and P) and Mann-Whitney U test (H, I, Q, and R): *P < 0.05, **P < 0.01 versus vehicle. Scale bars: 200 μm.