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Am J Physiol Endocrinol Metab. 2018 Nov 1;315(5):E833-E847. doi: 10.1152/ajpendo.00182.2018. Epub 2018 Jun 26.

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

Author information

1
Service of Endocrinology, Diabetology, and Metabolism, Department of Physiology, Faculty of Biology and Medicine, Lausanne University Hospital, University of Lausanne , Lausanne , Switzerland.
2
Clinical Chemistry Laboratory, Faculty of Biology and Medicine, Lausanne University Hospital, University of Lausanne , Lausanne , Switzerland.
3
Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospital and Faculty of Medicine , Geneva , Switzerland.
4
Service of Endocrinology, Diabetes, Hypertension, and Nutrition, Geneva University Hospital and Faculty of Medicine , Geneva , Switzerland.
5
Institute of Microbiology, Faculty of Biology and Medicine, Lausanne University Hospital, University of Lausanne , Lausanne , Switzerland.
6
Department of Physiology, Faculty of Biology and Medicine, University of Lausanne , Lausanne , Switzerland.
7
Institute of Pathology, Faculty of Biology and Medicine, Lausanne University Hospital, University of Lausanne , Lausanne , Switzerland.

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).

KEYWORDS:

bile acid; deoxycholic acid; fibroblast growth factor; inflammation; β-Klotho

PMID:
29944388
DOI:
10.1152/ajpendo.00182.2018

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