Induced hypothyroidism accelerates the regression of liver fibrosis in rats.
OBJECTIVE
It has been shown in previous studies that hypothyroidism prevents the development of liver fibrosis in bile duct ligated rats and in rats chronically treated with thioacetamide (TAA). In recent years, regression of liver fibrosis (occurring spontaneously or during treatment) has been demonstrated in rodent models such as bile duct ligation and CCl(4) administration. Therefore, in the present study, the potential therapeutic effect of hypothyroidism on liver fibrosis was investigated.


METHODS
Liver fibrosis was induced in rats by administration of TAA (200 mg/kg, i.p., twice weekly) for 12 weeks. Hypothyroidism was then induced by either methimazole (0.04%) or propylthiouracil (0.05%) administered in drinking water for 8 weeks. Control euthyroid rats received normal drinking water. Hypothyroidism was confirmed by a significant elevation of serum thyroid-stimulating hormone levels.


RESULTS
Eight weeks after the cessation of TAA administration, spleen weight, histological score of liver fibrosis, and hepatic hydroxyproline content were significantly lower in both groups of hypothyroid rats as compared to euthyroid controls (P < 0.001). In vitro studies using the rat hepatic stellate cell line HSC-T6 using northern blot analysis and zymography, respectively, showed that high concentrations of triiodotyronine (T(3)) enhanced transforming growth factor (TGF)-beta-induced collagen I gene expression, and reduced metalloproteinase (MMP)-2 secretion, implying that reducing the levels of T(3) may contribute to resolution of fibrosis. Additionally, low T(3) concentration inhibited HSC-T6 proliferation.


CONCLUSIONS
Pharmacologically induced hypothyroidism accelerates the resolution of liver fibrosis in rats. This beneficial effect may in part be due to prevention of T(3)-induced stimulation of collagen synthesis and reduction of MMP-2 secretion.
Bruck
Rafael
R
Department of Gastrointestinal and Liver Diseases, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel. rafib@tasmc.health.gov.il
Weiss
Sigal
S
Traister
Alexandra
A
Zvibel
Isabel
I
Aeed
Hussein
H
Halpern
Zamir
Z
Oren
Ran
R
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D007037:Hypothyroidism / Q000139:chemically induced / Q000150:complications*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000150:complications*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014284:Triiodothyronine / Q000494:pharmacology
D024042:Collagen Type I; D016212:Transforming Growth Factor beta; D014284:Triiodothyronine; D020778:Matrix Metalloproteinase 2