PMID- 33231505 OWN - NLM STAT- MEDLINE DCOM- 20220119 LR - 20231213 IS - 1557-9077 (Electronic) IS - 1050-7256 (Linking) VI - 31 IP - 6 DP - 2021 Jun TI - Hypothyroidism Increases Cholesterol Gallstone Prevalence in Mice by Elevated Hydrophobicity of Primary Bile Acids. PG - 973-984 LID - 10.1089/thy.2020.0636 [doi] AB - 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. FAU - Kube, Irina AU - Kube I AD - Department of Endocrinology, Diabetes and Metabolism and Clinical Chemistry, Division of Laboratory Research, University of Duisburg-Essen, Essen, Germany. FAU - Tardio, Luca Bartolomeo AU - Tardio LB AD - Department of Endocrinology, Diabetes and Metabolism and Clinical Chemistry, Division of Laboratory Research, University of Duisburg-Essen, Essen, Germany. FAU - Hofmann, Ute AU - Hofmann U AD - Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tubingen, Stuttgart, Germany. FAU - Ghallab, Ahmed AU - Ghallab A AD - Department of Toxicology/Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Dortmund, Germany. AD - Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt. FAU - Hengstler, Jan G AU - Hengstler JG AD - Department of Toxicology/Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Dortmund, Germany. FAU - Fuhrer, Dagmar AU - Fuhrer D AD - Department of Endocrinology, Diabetes and Metabolism and Clinical Chemistry, Division of Laboratory Research, University of Duisburg-Essen, Essen, Germany. FAU - Zwanziger, Denise AU - Zwanziger D AD - Department of Endocrinology, Diabetes and Metabolism and Clinical Chemistry, Division of Laboratory Research, University of Duisburg-Essen, Essen, Germany. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210105 PL - United States TA - Thyroid JT - Thyroid : official journal of the American Thyroid Association JID - 9104317 RN - 0 (ABCG5 protein, mouse) RN - 0 (ATP Binding Cassette Transporter, Subfamily B) RN - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 11) RN - 0 (ATP Binding Cassette Transporter, Subfamily G, Member 5) RN - 0 (Abcb11 protein, mouse) RN - 0 (Bile Acids and Salts) RN - 0 (Lipoproteins) RN - 0 (Phosphatidylcholines) RN - 97C5T2UQ7J (Cholesterol) RN - EC 1.1.1.- (Hydroxymethylglutaryl CoA Reductases) RN - EC 1.1.1.34 (Hmgcr protein, mouse) RN - EC 1.14.14.23 (Cholesterol 7-alpha-Hydroxylase) RN - EC 1.14.14.23 (Cyp7a1 protein, mouse) RN - EC 2.7.7.15 (Choline-Phosphate Cytidylyltransferase) RN - EC 2.7.7.15 (Pcyt1a protein, mouse) SB - IM MH - ATP Binding Cassette Transporter, Subfamily B/metabolism MH - ATP Binding Cassette Transporter, Subfamily B, Member 11/metabolism MH - ATP Binding Cassette Transporter, Subfamily G, Member 5/metabolism MH - Animals MH - Bile Acids and Salts/biosynthesis/*metabolism MH - Cholelithiasis/genetics/metabolism/pathology MH - Cholesterol/biosynthesis/*metabolism MH - Cholesterol 7-alpha-Hydroxylase/genetics MH - Choline-Phosphate Cytidylyltransferase/genetics MH - Gallbladder/*metabolism/pathology MH - Gallstones/genetics/*metabolism/pathology MH - Hydrophobic and Hydrophilic Interactions MH - Hydroxymethylglutaryl CoA Reductases/genetics MH - Hypothyroidism/genetics/*metabolism MH - Lipoproteins/metabolism MH - Liver/*metabolism/pathology MH - Mice MH - Phosphatidylcholines/biosynthesis/metabolism MH - ATP-Binding Cassette Sub-Family B Member 4 OTO - NOTNLM OT - bile acids OT - detoxification phase II OT - sulfonation OT - thyroid dysfunction OT - thyroid hormones EDAT- 2020/11/25 06:00 MHDA- 2022/01/20 06:00 CRDT- 2020/11/24 12:10 PHST- 2020/11/25 06:00 [pubmed] PHST- 2022/01/20 06:00 [medline] PHST- 2020/11/24 12:10 [entrez] AID - 10.1089/thy.2020.0636 [doi] PST - ppublish SO - Thyroid. 2021 Jun;31(6):973-984. doi: 10.1089/thy.2020.0636. Epub 2021 Jan 5.