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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiposity / genetics
  • Animals
  • Bile Acids and Salts / metabolism*
  • Body Weight / physiology*
  • Energy Metabolism / genetics
  • Fibroblast Growth Factors / metabolism
  • Gastrointestinal Tract / metabolism*
  • Gluconeogenesis / physiology
  • Ketone Bodies / blood
  • Liver / metabolism*
  • Liver Cirrhosis / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Signal Transduction / physiology

Substances

  • Bile Acids and Salts
  • Ketone Bodies
  • Klb protein, mouse
  • Membrane Proteins
  • fibroblast growth factor 15, mouse
  • fibroblast growth factor 21
  • Fibroblast Growth Factors