Bile-acid-mediated decrease in endoplasmic reticulum stress: a potential contributor to the metabolic benefits of ileal interposition surgery in UCD-T2DM rats

Authors

Bethany P. Cummings, University of California DavisFollow
Ahmed Bettaieb, University of California Davis
James L. Graham, University of California Davis
Jaehyoung Kim, University of Nebraska-LincolnFollow
Fangrui Ma, University of Nebraska-LincolnFollow
Noreene Shibata, University of California Davis
Kimber L. Stanhope, University of California Davis
Cecilia Giulivi, University of California Davis
Frederik Hansen, Gubra ApS, 2970 Hørsholm, Denmark
Jacob Jelsing, Gubra ApS, 2970 Hørsholm, Denmark
Niels Vrang, Gubra ApS, 2970 Hørsholm, Denmark
Mark Kowala, Lilly Research Laboratories
Michael L. Chouinard, Lilly Research Laboratories
Fawaz G. Haj, University of California Davis
Peter J. Havel, University of California Davis

Date of this Version

2013

Document Type

Article

Citation

Disease Models & Mechanisms 6, 443-456 (2013) doi:10.1242/dmm.010421

Comments

© 2013. Published by The Company of Biologists Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License

Abstract

Post-operative increases in circulating bile acids have been suggested to contribute to the metabolic benefits of bariatric surgery; however, their mechanistic contributions remain undefined. We have previously reported that ileal interposition (IT) surgery delays the onset of type 2 diabetes in UCD-T2DM rats and increases circulating bile acids, independently of effects on energy intake or body weight. Therefore, we investigated potential mechanisms by which post-operative increases in circulating bile acids improve glucose homeostasis after IT surgery. IT, sham or no surgery was performed on 2-month-old weight-matched male UCD-T2DM rats. Animals underwent an oral fat tolerance test (OFTT) and serial oral glucose tolerance tests (OGTT). Tissues were collected at 1.5 and 4.5 months after surgery. Cell culture models were used to investigate interactions between bile acids and ER stress. IT-operated animals exhibited marked improvements in glucose and lipid metabolism, with concurrent increases in postprandial glucagon-like peptide-1 (GLP-1) secretion during the OFTT and OGTTs, independently of food intake and body weight. Measurement of circulating bile acid profiles revealed increases in circulating total bile acids in IT-operated animals, with a preferential increase in circulating cholic acid concentrations. Gut microbial populations were assessed as potential contributors to the increases in circulating bile acid concentrations, which revealed proportional increases in Gammaproteobacteria in IT-operated animals. Furthermore, IT surgery decreased all three sub-arms of ER stress signaling in liver, adipose and pancreas tissues. Amelioration of ER stress coincided with improved insulin signaling and preservation of β-cell mass in IT-operated animals. Incubation of hepatocyte, adipocyte and β-cell lines with cholic acid decreased ER stress. These results suggest that postoperative increases in circulating cholic acid concentration contribute to improvements in glucose homeostasis after IT surgery by ameliorating ER stress.