Suppression of bile acid synthesis by thyroid hormone in primary human hepatocytes.
OBJECTIVE
It is known that thyroid hormones alter the bile acid metabolism in humans, however the effect on individual enzymes has been difficult to elucidate. This is mainly due to the lack of human liver cell lines producing bile acids. We used cultures of primary human hepatocytes to study the effects of triiodothyronine (T(3)) on bile acid synthesis.


METHODS
Primary hepatocytes were isolated from liver tissue obtained from three different patients undergoing liver resection due to underlying malignancy. The hepatocytes were cultured under serum-free conditions and treated from d 1 to d 5 with culture containing 0.1 - 1000 nmol/L of T(3). Bile acid formation and mRNA levels of key enzymes were analysed.


RESULTS
The lowest concentration of T(3) decreased cholic acid (CA) formation to 43%-53% of controls and chenodeoxycholic acid (CDCA) to 52%-75% of controls on d 5. The highest dose further decreased CA formation to 16%-48% of controls while CDCA formation remained at 50%-117% of controls. Expression of mRNA levels of cholesterol 7alpha-hydroxylase (CYP7A1) and sterol 12alpha-hydroxylase (CYP8B1) dose-dependently decreased. Sterol 27-hydroxylase (CYP27A1) levels also decreased, but not to the same extent.


CONCLUSIONS
T(3) dose-dependently decreased total bile acid formation in parallel with decreased expression of CYP7A1 and CYP8B1. CA formation is inhibited to a higher degree than CDCA, resulting in a marked decrease in the CA /CDCA ratio.
Ellis
Ewa Cristine Siljevik
EC
Department of Pathology, University of Pittsburgh, 200 Lothrop Street, Biomedical Science Tower S-450, Pittsburgh, PA 152 61, USA. ece5@pitt.edu
D001647:Bile Acids and Salts / Q000096:biosynthesis*; D002478:Cells, Cultured; D002635:Chenodeoxycholic Acid / Q000378:metabolism; D053493:Cholestanetriol 26-Monooxygenase; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D019826:Cholic Acid / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013253:Steroid 12-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D014284:Triiodothyronine / Q000502:physiology*
D001647:Bile Acids and Salts; D012333:RNA, Messenger; D014284:Triiodothyronine; D002635:Chenodeoxycholic Acid; D013250:Steroid Hydroxylases; D002790:Cholesterol 7-alpha-Hydroxylase; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; D013253:Steroid 12-alpha-Hydroxylase; D019826:Cholic Acid