Deoxycholic acid supplementation impairs glucose homeostasis in mice

<div><p>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 <i>in vivo</i> 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.</p></div

DCA increases hepatic ER stress signaling and decreases hepatic insulin signaling.

<p>Phosphorylated to total IRE (A) and spliced XBP1 (sXBP1) expression normalized to tubulin (B). BiP (C) and TNFα (D) expression normalized to tubulin and phosphorylated to total Akt expression (E). Data are expressed as mean ± SEM, *<i>P</i><0.05, **<i>P</i><0.01 by Student’s t-test, <i>n</i> = 6 per group.</p

DCA supplementation impairs glucose homeostasis.

<p>Absolute blood glucose concentrations (A) and percentage change from baseline blood glucose concentrations (B) during an insulin tolerance test. (C) Blood glucose concentrations during an oral glucose tolerance test. Data are expressed as mean ± SEM, *<i>P</i><0.05 by two-factor ANOVA, ^#<i>P</i><0.05 by Student’s t-test, <i>n</i> = 8 per group.</p

Fasting serum bile acid profile.

<p>Total bile acid concentration (A), 12αOH:non-12αOH ratio (B) and hydrophobicity index (C) in fasting serum samples. Relative proportions of bile acid subtypes in fasting serum samples from HFD (D) and DCA treated (E) mice. Data are expressed as mean ± SEM, **<i>P</i><0.01, ****<i>P</i><0.0001 by Student’s t-test, <i>n</i> = 6 per group. TCA, taurocholic acid; TLCA, taurolitocholic acid; HDCA, hyodeoxycholic acid; GUDCA, glycoursodeoxycholic acid; CDCA, chenodeoxycholic acid; UDCA, ursodeoxycholic acid; αω MCA, αω muricholic acid; βMCA, β-muricholic acid and Tαβ MCA, tauro-αβ muricholic acid.</p

Food intake, body weight and adiposity.

<p>Energy intake (days 1–17, A), body weight (B), body weight gain (C) and adipose depot weights (subcutaneous (SQ), mesenteric (Mes), epididymal (Epi), retroperitoneal (RP) and brown adipose tissue (BAT)) (D). Data are expressed as mean ± SEM, <i>n</i> = 6 per group.</p