Abstract

Bile acids are critical contributors to the regulation of whole body glucose homeostasis; however, the mechanisms remain incompletely defined. While the hydrophilic bile acid subtype, ursodeoxycholic acid, has been shown to attenuate hepatic endoplasmic reticulum (ER) stress and thereby improve glucose regulation in mice, the effect of hydrophobic bile acid subtypes on ER stress and glucose regulation in vivo is unknown. Therefore, we investigated the effect of the hydrophobic bile acid subtype, deoxycholic acid (DCA), on ER stress and glucose regulation. Eight week old C57BL/6J mice were fed a high fat diet supplemented with or without DCA. Glucose regulation was assessed by oral glucose tolerance and insulin tolerance testing. In addition, circulating bile acid profile and hepatic insulin and ER stress signaling were measured. DCA supplementation did not alter body weight or food intake, but did impair glucose regulation. Consistent with the impairment in glucose regulation, DCA increased the hydrophobicity of the circulating bile acid profile, decreased hepatic insulin signaling and increased hepatic ER stress signaling. Together, these data suggest that dietary supplementation of DCA impairs whole body glucose regulation by disrupting hepatic ER homeostasis in mice.

Highlights

  • Bile acids are amphipathic steroid molecules with a well-defined role in the digestion and absorption of dietary lipid [1]

  • We find that deoxycholic acid (DCA) increases circulating bile acid profile hydrophobicity, increases hepatic endoplasmic reticulum (ER) stress and reduces hepatic insulin signaling, independently of body weight

  • In vivo assessment of glucose and insulin tolerance demonstrated that DCA supplementation impairs glucose homeostasis, independently of body weight

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Summary

Introduction

Bile acids are amphipathic steroid molecules with a well-defined role in the digestion and absorption of dietary lipid [1]. Bile acids have been shown to play a critical role in the regulation of glucose homeostasis [2]. The mechanisms by which bile acids regulate glucose homeostasis remain incompletely defined. Bile acid synthesis in the liver involves a series of enzymatic reactions during which the cholesterol sterol ring is modified and the side chain is shortened to produce the primary bile acids: cholic acid (CA) and chenodeoxycholic acid (CDCA) [3]. These primary bile acids are conjugated with either glycine or taurine and stored in the gallbladder [4]. Primary bile acids are secreted into the gastrointestinal tract, where they are subsequently deconjugated, dehydroxylated and oxidized in the distal intestinal lumen by gut microbes to generate

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