Absence of cholesterol gallstone formation in male C57BL/6 mice by abrogation of hepatic thyroid hormone action

Thyroid hormone (TH) impacts the hepatobiliary system. Epidemiological studies suggest a link between thyroid dysfunction and cholestatic liver disease. In previous studies we could confirm that a severe systemic TH deficiency promotes cholesterol gallstones. Using the lithogenic mouse model, we investigate whether changes in the systemic TH status or abrogation of hepatic TH action impact cholestatic liver disease.

Male C57BL/6 wildtype (WT) mice received a six weeks lithogenic diet either under iodine sufficient or deficient condition. Male hepatocyte specific TRβ knockout (hepTRβKO) mice received a six weeks lithogenic diet to investigate the role of abrogated hepatic TH action. Biliary cholesterol gallstone and crystal prevalence, liver histology, liver and thyroid functions test, TH- and cholestasis-responsive markers were evaluated.

Cholesterol gallstones were observed in lithogenic diet supplemented WT mice under iodine sufficient condition. In the iodine deficient group, a higher prevalence of cholesterol gallstone formation was observed, and the low iodine regiment reduced both systemic TH concentration and hepatic deiodinase 1 (Dio1) mRNA expression. In hepTRβKO a six-week lithogenic diet treatment could not induce macroscopic visible cholesterol gallstones, whereas a reduced lipid content and elevated gene expression of the cytochrome P450 enzyme Cyp2c39 were observed.

Systemic TH deficiency increases the pro-lithogenic response of male mice. Abrogation of hepatic TH action in male hepTRβKO mice shows an anti-lithogenic effect with an elevated expression of hepatic Cyp2c39 encoding for an n-3 fatty acid producing enzyme. The results provide new insights into the regulatory principle of local TH action in the hepatobiliary system.

Publication History

Article published online:
20 January 2025