Hypothyroidism Increases Cholesterol Gallstone Prevalence in Mice by Elevated Hydrophobicity of Primary Bile Acids

Thyroid. 2021 Jun;31(6):973-984. doi: 10.1089/thy.2020.0636. Epub 2021 Jan 5.

Abstract

Background: Thyroid hormone (TH) deficiency has been associated with increased cholesterol gallstone prevalence. Hypothyroidism impacts hepatic lipid homeostasis, biliary secretion, gallbladder motility, and gallstone (LITH) gene expression, all potential factors contributing to cholesterol gallstone disease (CGD). However, how TH deficiency may lead to gallstone formation is still poorly understood. Therefore, we performed molecular studies in a CGD mouse model under lithogenic conditions and modulation of TH status. Methods: Male, three-month-old C57BL/6 mice were randomly divided into a control (euthyroid) group, a hypothyroid (hypo) group, a gallstone (litho) group, and a gallstone+hypothyroid (litho+hypo) group and were treated for 2, 4, and 6 weeks (n = 8/treatment period). Gallstone prevalence, biliary composition and cholesterol crystals, hepatic expression of genes participating in cholesterol, bile acid (BA), and phosphatidylcholine synthesis (Hmgcr, Cyp7a1, Pcyt1a), and canalicular transport (Abcg5, Bsep, Abcb4) were investigated. Results: Increased cholesterol gallstone prevalence was observed in hypothyroid mice under lithogenic diet after 4 and 6 weeks of treatment (4 weeks: 25% vs. 0%; 6 weeks: 75% vs. 37.5%). Interestingly, neither the composition of the three main biliary components, cholesterol, BAs, and phosphatidylcholine, nor the hepatic expression of genes involved in synthesis and transport could explain the differences in cholesterol gallstone formation in the mice. However, TH deficiency resulted in significantly increased hydrophobicity of primary BAs in bile. Furthermore, downregulation of hepatic sulfonation enzymes Papss2 and Sult2a8 as well as diminished biliary BA sulfate concentrations in mice were observed under hypothyroid conditions all contributing to a lithogenic biliary milieu as evidenced by microscopic cholesterol crystals and macroscopic gallstone formation. Conclusions: We describe a novel pathogenic link between TH deficiency and CGD and suggest that the increased hydrophobic character of biliary BAs due to the diminished expression of hepatic detoxification enzymes promotes cholesterol crystal precipitation and enhances cholesterol gallstone formation in the bile of hypothyroid mice.

Keywords: bile acids; detoxification phase II; sulfonation; thyroid dysfunction; thyroid hormones.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • ATP Binding Cassette Transporter, Subfamily B, Member 11 / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 5 / metabolism
  • ATP-Binding Cassette Sub-Family B Member 4
  • Animals
  • Bile Acids and Salts / biosynthesis
  • Bile Acids and Salts / metabolism*
  • Cholelithiasis / genetics
  • Cholelithiasis / metabolism
  • Cholelithiasis / pathology
  • Cholesterol / biosynthesis
  • Cholesterol / metabolism*
  • Cholesterol 7-alpha-Hydroxylase / genetics
  • Choline-Phosphate Cytidylyltransferase / genetics
  • Gallbladder / metabolism*
  • Gallbladder / pathology
  • Gallstones / genetics
  • Gallstones / metabolism*
  • Gallstones / pathology
  • Hydrophobic and Hydrophilic Interactions
  • Hydroxymethylglutaryl CoA Reductases / genetics
  • Hypothyroidism / genetics
  • Hypothyroidism / metabolism*
  • Lipoproteins / metabolism
  • Liver / metabolism*
  • Liver / pathology
  • Mice
  • Phosphatidylcholines / biosynthesis
  • Phosphatidylcholines / metabolism

Substances

  • ABCG5 protein, mouse
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • ATP Binding Cassette Transporter, Subfamily G, Member 5
  • Abcb11 protein, mouse
  • Bile Acids and Salts
  • Lipoproteins
  • Phosphatidylcholines
  • Cholesterol
  • Hydroxymethylglutaryl CoA Reductases
  • Hmgcr protein, mouse
  • Cholesterol 7-alpha-Hydroxylase
  • Cyp7a1 protein, mouse
  • Choline-Phosphate Cytidylyltransferase
  • Pcyt1a protein, mouse