Endocrine Abstracts

Objectives: Cholesterol gallstone disease has a prevalence of 10-15% being one of the most common gastrointestinal pathologies. It is well known that thyroid hormone (TH) impacts the hepatobiliary system. Epidemiological studies suggest a link between thyroid dysfunction and cholestatic liver disease. In our previous studies we could confirm that a severe systemic TH deficiency promotes cholesterol gallstone formation in C57BL/6 mice. Using the lithogenic mouse model, in the present study we investigate whether more subtle changes in the systemic TH status or abrogation of hepatic TH action impact cholestatic liver disease.

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

Results: Cholesterol gallstones were observed in lithogenic diet supplemented WT mice under iodine sufficient condition (57%). In the iodine deficient group, a higher prevalence of cholesterol gallstone formation (80%) was observed, and the low iodine regiment reduced both systemic TH concentration and hepatic deiodinase 1 (Dio1) mRNA expression. In hepTRβKO mice successful abrogation of hepatic TH action was determined, whereas systemic TH status was not altered. A six-week lithogenic diet treatment could not induce macroscopic visible cholesterol gallstones in hepTRβKO mice which cannot be explained by cholestasis-responsive markers. In hepTRβKO mice a reduced lipid content and elevated gene expression of the cytochrome P450 enzyme Cyp2c39 was observed.

Conclusions and outlook: Systemic TH deficiency increases the pro-lithogenic response of male C57BL/6 mice leading to a higher cholesterol gallstone prevalence. Abrogation of hepatic TH action in male hepTRβKO mice shows an anti-lithogenic effect by preventing mice against cholesterol gallstone formation. This is associated 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.