Dr. Denise Zwanziger
Role of Tight Junctions in Gallstone Formation under Hypothyroidism
Hypothyroidism is frequently associated with hepatic alterations as the liver is the site of thyroid hormone metabolism. Moreover, in hypothyroidism the risk for gallstone diseases and common bile duct stones is increased. A recent publication analyzed the association between thyroid function and the risk of cholelithiasis using data on an epidemiological study (SHIP). In this study a relation of high serum TSH concentrations with cholelithiasis among men was found whereas in women no such association could be observed. In contrast, without thyroid dysfunction normally women are more affected to develop gallstones than men. This leads to the hypothesis of a gender-specific relation between hypothyroidism and gallstone diseases. Tight junction (TJ) proteins like claudin-1 and claudin-2 are involved in the regulation of the paracellular barrier integrity and paracellular permeability between epithelial cells. Biliary diseases can be associated with altered human claudin-1 expression or mutation and claudin-2 deficiency has been found to be relevant in murine cholesterol gallstone formation. In preliminary experiments we found that murine hepatic claudin-1 and claudin-2 expression patterns are influenced by hypothyroidism in a sex-dependent manner. Under hypothyroidism hepatic claudin-1 and claudin-2 protein levels were decreased in male mice, whereas an increase of hepatic claudin-1 and claudin-2 protein levels could be observed in female mice. Moreover, in the euthyroid state female mice express less hepatic claudin-1 and claudin-2 than male mice. Therefore, we hypothesize that the diminished hepatic claudin-1 and claudin-2 expressions in hypothyroid male mice and the already known increased risk of human biliary diseases by low claudin-1 as well as the increased murine susceptibility of gallstone formation by lacking claudin-2 could explain why gallstone diseases are more frequent in hypothyroid men than women. Within this proposed project we will investigate the role and functional mechanism of TJ in gallstone formation under hypothyroidism by using a gallstone-susceptible mouse model. Furthermore, by this project novel molecular markers for thyroid hormone related gallstone formation will be obtained by transcriptome and proteome analysis. These results will lead to a better understanding of the pathogenic character of gallstone diseases by thyroid dysfunction and are also of important interest within the Thyroid Trans Act SPP 1629 program which is focused on aspects of thyroid hormone related diseases.