β-Klotho deficiency shifts the gut-liver bile acid axis and induces hepatic alterations in mice.

Details

Serval ID
serval:BIB_4784D51A916B
Type
Article: article from journal or magazin.
Collection
Publications
Title
β-Klotho deficiency shifts the gut-liver bile acid axis and induces hepatic alterations in mice.
Journal
American journal of physiology. Endocrinology and metabolism
Author(s)
Somm E., Henry H., Bruce S.J., Bonnet N., Montandon S.A., Niederländer N.J., Messina A., Aeby S., Rosikiewicz M., Fajas L., Sempoux C., Ferrari S.L., Greub G., Pitteloud N.
ISSN
1522-1555 (Electronic)
ISSN-L
0193-1849
Publication state
Published
Issued date
01/11/2018
Peer-reviewed
Oui
Volume
315
Number
5
Pages
E833-E847
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
β-Klotho (encoded by Klb) is an obligate coreceptor, mediating both fibroblast growth factor (FGF)15 and FGF21 signaling. Klb <sup>-/-</sup> mice are refractory to metabolic FGF15 and FGF21 action and exhibit derepressed (increased) bile acid (BA) synthesis. Here, we deeply phenotyped male Klb <sup>-/-</sup> mice on a pure C57BL/6J genetic background, fed a chow diet focusing on metabolic aspects. This aims to better understand the physiological consequences of concomitant FGF15 and FGF21 signaling deficiency, in particular on the gut-liver axis. Klb <sup>-/-</sup> mice present permanent growth restriction independent of adiposity and energy balance. Klb <sup>-/-</sup> mice also exhibit few changes in carbohydrate metabolism, combining normal gluco-tolerance, insulin sensitivity, and fasting response with increased gluconeogenic capacity and decreased glycogen mobilization. Livers of Klb <sup>-/-</sup> mice reveal pathologic features, including a proinflammatory status and initiation of fibrosis. These defects are associated to a massive shift in BA composition in the enterohepatic system and blood circulation featured by a large excess of microbiota-derived deoxycholic acid, classically known for its genotoxicity in the gastrointestinal tract. In conclusion, β-Klotho is a gatekeeper of hepatic integrity through direct action (mediating FGF21 anti-inflammatory signaling) and indirect mechanisms (mediating FGF15 signaling that maintains BA level and composition).
Keywords
Beta-Klotho, Bile acid, Deoxycholic acid, Fibroblast Growth Factor, inflammation, bile acid, deoxycholic acid, fibroblast growth factor, β-Klotho
Pubmed
Web of science
Create date
29/06/2018 17:23
Last modification date
20/08/2019 14:53
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