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β-Klotho deficiency shifts the gut-liver bile acid axis and induces hepatic alterations in mice.
- Source :
-
American Journal of Physiology: Endocrinology & Metabolism . Nov2018, Vol. 315 Issue 5, pE833-E847. 15p. 1 Chart, 6 Graphs. - Publication Year :
- 2018
-
Abstract
- β-Klotho (encoded by Klb) is an obligate coreceptor, mediating both fibroblast growth factor (FGF)15 and FGF21 signaling. Klb-/- mice are refractory to metabolic FGF15 and FGF21 action and exhibit derepressed (increased) bile acid (BA) synthesis. Here, we deeply phenotyped male Klb-/- 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-/- mice present permanent growth restriction independent of adiposity and energy balance. Klb-/- 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-/- 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). [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 01931849
- Volume :
- 315
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- American Journal of Physiology: Endocrinology & Metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 158395425
- Full Text :
- https://doi.org/10.1152/ajpendo.00182.2018