title: Endoplasmic Reticulum Stress Regulates Hepatic Bile Acid Metabolism in Mice.
abstract: OBJECTIVE
  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 ofCyp7a1,Abcb11, andAbcc3occurred 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.
authors.affiliation: Division of Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Anne S
authors.initials: AS
authors.lastname: Henkel
authors.affiliation: Division of Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Brian
authors.initials: B
authors.lastname: LeCuyer
authors.affiliation: Division of Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Shantel
authors.initials: S
authors.lastname: Olivares
authors.affiliation: Division of Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Green
keywords: 7α-Hydroxy-4-Cholesten-3-1; ABC, adenosine triphosphate binding cassette; Bile Acid Synthesis; C4, 7α-hydroxy-4-cholesten-3-1; CYP7A1, cholesterol 7α-hydroxylase; Cyp7a1; DMEM, Dulbecco's modified Eagle medium; DMSO, dimethyl sulfoxide; ER, endoplasmic reticulum; ERK, extracellular signaling-regulated kinase; FGF, fibroblast growth factor; FXR, farnesoid X receptor; IL, interleukin; IRE1α, inositol requiring enzyme 1α; JNK, c-Jun-N-terminal kinase; NTCP, sodium/taurocholate cotransporter; RIDD, regulated inositol requiring enzyme 1α–dependent messenger RNA decay; SHP, small heterodimer partner; UPR, unfolded protein response; Unfolded Protein Response; mRNA, messenger RNA