Endoplasmic Reticulum Stress Regulates Hepatic Bile Acid Metabolism in Mice

• Published in: Cellular and molecular gastroenterology and hepatology Vol. 3; no. 2; pp. 261 - 271
• Main Authors: Henkel, Anne S, LeCuyer, Brian, Olivares, Shantel, Green, Richard M
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2017; Elsevier
• Subjects: 7α-Hydroxy-4-Cholesten-3-1; Bile Acid Synthesis; Cyp7a1; Gastroenterology and Hepatology; Original Research; Unfolded Protein Response; FXR; ABC; 7α-Hydroxy-4-Cholesten-3-1; DMSO; JNK; mRNA; C4; DMEM; RIDD; dimethyl sulfoxide; fibroblast growth factor; messenger RNA; UPR; cholesterol 7α-hydroxylase; NTCP; Bile Acid Synthesis; SHP; adenosine triphosphate binding cassette; sodium/taurocholate cotransporter; regulated inositol requiring enzyme 1α–dependent messenger RNA decay; interleukin; c-Jun-N-terminal kinase; extracellular signaling-regulated kinase; Dulbecco's modified Eagle medium; IL; FGF; farnesoid X receptor; inositol requiring enzyme 1α; Unfolded Protein Response; ER; IRE1α; small heterodimer partner; Cyp7a1; endoplasmic reticulum; ERK; CYP7A1, cholesterol 7α-hydroxylase; mRNA, messenger RNA; FXR, farnesoid X receptor; RIDD, regulated inositol requiring enzyme 1α–dependent messenger RNA decay; FGF, fibroblast growth factor; IRE1α, inositol requiring enzyme 1α; JNK, c-Jun-N-terminal kinase; C4, 7α-hydroxy-4-cholesten-3-1; DMEM, Dulbecco's modified Eagle medium; UPR, unfolded protein response; ABC, adenosine triphosphate binding cassette; ERK, extracellular signaling-regulated kinase; SHP, small heterodimer partner; IL, interleukin; DMSO, dimethyl sulfoxide; NTCP, sodium/taurocholate cotransporter; ER, endoplasmic reticulum
• ISSN: 2352-345X; 2352-345X
• DOI: 10.1016/j.jcmgh.2016.11.006

Background & Aims Cholestasis promotes endoplasmic reticulum (ER) stress in the liver, however, the effect of ER stress on hepatic bile acid metabolism is unknown. We aim to determine the effect of ER stress on hepatic bile acid synthesis and transport in mice. Methods ER stress was induced pharmacologically in C57BL/6J mice and human hepatoma (HepG2) cells. The hepatic expression of genes controlling bile acid synthesis and transport was determined. To measure the activity of the primary bile acid synthetic pathway, the concentration of 7α-hydroxy-4-cholesten-3-1 was measured in plasma. Results Induction of ER stress in mice and HepG2 cells rapidly suppressed the hepatic expression of the primary bile acid synthetic enzyme, cholesterol 7α-hydroxylase. Plasma levels of 7α-hydroxy-4-cholesten-3-1 were reduced in mice subjected to ER stress, indicating impaired bile acid synthesis. Induction of ER stress in mice and HepG2 cells increased expression of the bile salt export pump (adenosine triphosphate binding cassette [ Abc ] b11 ) and a bile salt efflux pump ( Abcc3 ). The observed regulation of Cyp7a1 , Abcb11 , and Abcc3 occurred in the absence of hepatic inflammatory cytokine activation and was not dependent on activation of hepatic small heterodimer partner or intestinal fibroblast growth factor 15. Consistent with suppressed bile acid synthesis and enhanced bile acid export from hepatocytes, prolonged ER stress decreased the hepatic bile acid content in mice. Conclusions Induction of ER stress in mice suppresses bile acid synthesis and enhances bile acid removal from hepatocytes independently of established bile acid regulatory pathways. These data show a novel function of the ER stress response in regulating bile acid metabolism.