Activation of Constitutive Androstane Receptor Prevents Cholesterol Gallstone Formation

Am J Pathol. 2017 Apr;187(4):808-818. doi: 10.1016/j.ajpath.2016.12.013. Epub 2017 Mar 7.

Abstract

Cholesterol gallstone disease (CGD) is one of the most common gastrointestinal diseases. Lithogenic hepatic bile secretion precedes the formation of cholesterol gallstones. Constitutive androstane receptor (CAR), a member of nuclear family, plays an important role in cholesterol and bile acid metabolism. To examine whether activation of CAR can prevent cholesterol gallstone formation, we treated C57BL6/J mice maintained on a lithogenic diet with CAR agonist 1,4-bis-[2-(3, 5-dichlorpyridyloxy)] benzene and performed bile duct cannulation to study the dynamics of biliary lipids. We report that activation of CAR decreases the biliary cholesterol concentration and prevents CGD formation. The lower biliary cholesterol level was largely attributed to suppressed Abcg5 and Abcg8 expression in CAR-activated mice. CAR activation also promoted cholesterol conversion into bile acids by increasing the expression of Cyp7a1, a rate-limiting enzyme in bile acid biosynthesis. Activation of CAR enhanced bile acid re-absorption via increasing the expression of bile acid transporters Asbt and Ostβ in the ileum. The hepatic steatosis was also improved in the liver of CAR-activated mice. Furthermore, activation of CAR protected the mice against the liver X receptor α-sensitized CGD through suppressing the expression of Abcg5/8. Collectively, CAR plays an important role in maintaining the homeostasis of cholesterol, bile acids, and triglycerides levels, and it might be a promising therapeutic target for preventing or treating CGD.

MeSH terms

  • Animals
  • Bile / metabolism
  • Bile Canaliculi / metabolism
  • Biological Transport / genetics
  • Cholesterol / adverse effects*
  • Cholesterol 7-alpha-Hydroxylase
  • Constitutive Androstane Receptor
  • Fatty Liver / genetics
  • Fatty Liver / pathology
  • Gallbladder / metabolism
  • Gallbladder / pathology
  • Gallstones / metabolism*
  • Gallstones / pathology
  • Gallstones / prevention & control*
  • Gene Expression Regulation
  • Lipogenesis / genetics
  • Liver / metabolism
  • Liver / pathology
  • Liver X Receptors / metabolism
  • Male
  • Mice, Inbred C57BL
  • Phospholipids / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Cytoplasmic and Nuclear / metabolism*

Substances

  • Constitutive Androstane Receptor
  • Liver X Receptors
  • Phospholipids
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Cholesterol
  • Cholesterol 7-alpha-Hydroxylase
  • Cyp7a1 protein, mouse