期刊
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
卷 315, 期 5, 页码 E833-E847出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00182.2018
关键词
beta-Klotho; bile acid; deoxycholic acid; fibroblast growth factor; inflammation
资金
- Swiss National Foundation [141960]
- Novartis Foundation for medical-biological Research [16A027]
beta-Klotho (encoded by Klb) is an obligate coreceptor, mediating both fibroblast growth factor (FGF)15 and FGF21 signaling. Mb' 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 C57BU/6J genetic back- ground, 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 glucotolerance, 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. beta-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).
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