| Creator |
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Jiang, Changtao
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Xie, Cen
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Lv, Ying
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Li, Jing
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Krausz, Kristopher W.
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Shik Jingmin
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Brocker, Chad N.
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Desai, Dhimant
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Amin, Shantu G.
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Bisson, William H.
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Liu, Yulan
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Gavrilova, Oksana
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Patterson, Andrew D.
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Gonzalez, Frank J.
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| Abstract |
- The farnesoid X receptor (FXR) regulates bile acid, lipid and glucose metabolism. Here we
show that treatment of mice with glycine-b-muricholic acid (Gly-MCA) inhibits FXR signalling
exclusively in intestine, and improves metabolic parameters in mouse models of obesity.
Gly-MCA is a selective high-affinity FXR inhibitor that can be administered orally and
prevents, or reverses, high-fat diet-induced and genetic obesity, insulin resistance and hepatic
steatosis in mice. The high-affinity FXR agonist GW4064 blocks Gly-MCA action in the gut,
and intestine-specific Fxr-null mice are unresponsive to the beneficial effects of Gly-MCA.
Mechanistically, the metabolic improvements with Gly-MCA depend on reduced biosynthesis
of intestinal-derived ceramides, which directly compromise beige fat thermogenic function.
Consequently, ceramide treatment reverses the action of Gly-MCA in high-fat diet-induced
obese mice. We further show that FXR signalling in ileum biopsies of humans positively
correlates with body mass index. These data suggest that Gly-MCA may be a candidate for
the treatment of metabolic disorders.
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| Rights Statement |
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| Additional Information |
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No. of bitstreams: 3
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- description.provenance : Made available in DSpace on 2015-12-16T21:57:37Z (GMT). No. of bitstreams: 3
license_rdf: 1370 bytes, checksum: cd1af5ab51bcc7a5280cf305303530e9 (MD5)
BissonWilliamEnvironMoleToxIntestineSelectiveFarnesoid.pdf: 2888956 bytes, checksum: 0ca708562126043797b8109fdbed8e52 (MD5)
BissonWilliamEnvironMoleToxIntestineSelectiveFarnesoid(Supplementary Figures 1-17, Supplementary Tables 1-3 and Supplementary Reference).pdf: 16936805 bytes, checksum: 7877fdd521ba22c062faf91763311ee6 (MD5)
Previous issue date: 2015-12-15
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