Suppressing the intestinal farnesoid X receptor/sphingomyelin phosphodiesterase 3 axis decreases atherosclerosis.
Animals
Atherosclerosis
/ chemically induced
Ceramides
/ biosynthesis
Diet, High-Fat
/ adverse effects
Female
Humans
Intestinal Mucosa
/ metabolism
Male
Mice
Mice, Knockout, ApoE
Receptors, Cytoplasmic and Nuclear
/ antagonists & inhibitors
Sphingomyelin Phosphodiesterase
/ genetics
Ursodeoxycholic Acid
/ analogs & derivatives
Atherosclerosis
Cardiology
Cardiovascular disease
Vascular Biology
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
03 05 2021
03 05 2021
Historique:
received:
03
08
2020
accepted:
11
03
2021
entrez:
3
5
2021
pubmed:
4
5
2021
medline:
6
10
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33938457
pii: 142865
doi: 10.1172/JCI142865
pmc: PMC8087211
doi:
pii:
Substances chimiques
Ceramides
0
Receptors, Cytoplasmic and Nuclear
0
farnesoid X-activated receptor
0C5V0MRU6P
glycoursodeoxycholic acid
64480-66-6
Ursodeoxycholic Acid
724L30Y2QR
SMPD3 protein, human
EC 3.1.4.12
Smpd3 protein, mouse
EC 3.1.4.12
Sphingomyelin Phosphodiesterase
EC 3.1.4.12
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIDDK NIH HHS
ID : U01 DK119702
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC005562
Pays : United States
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