{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T03:14:57Z","timestamp":1790997297766,"version":"4.1.0"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":4170,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2004,4]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>Thyrotoxicosis may be associated with a variety of abnormalities of liver function. The pathogenesis of hepatic dysfunction in thyrotoxicosis is unknown, but has been attributed to mitochondrial dysfunction. We studied the effect of altered thyroid function on the apoptotic index in rat liver. Extensive DNA fragmentation and significantly increased caspase-3 activity (<jats:italic toggle=\"yes\">P<\/jats:italic> &lt; .001) and caspase-9 activation (<jats:italic toggle=\"yes\">P<\/jats:italic> &lt; .005) were observed in hyperthyroid rat liver; cell death by apoptosis was confirmed. In hyperthyroid rat liver, 60% of mitochondria exhibited disruption of their outer membranes and a decrease in the number of cristae. These findings, along with significant translocation of cytochrome <jats:italic toggle=\"yes\">c<\/jats:italic> and second mitochondria-derived activator of caspases to cytosol (<jats:italic toggle=\"yes\">P<\/jats:italic> &lt; .005), suggest activation of a mitochondrial-mediated pathway. However, no change in the expression levels of Bcl-2, Bax, and Bcl-x<jats:sub>L<\/jats:sub> were found in hyperthyroidism. For <jats:italic toggle=\"yes\">in vitro<\/jats:italic> experiments, rat liver mitochondria were isolated and purified in sucrose density gradients and were treated with triiodothyronine (T3; 2-8 \u03bcM). T3 treatment resulted in an abrupt increase in mitochondrial permeability transition. Using a cell-free apoptosis system, the apoptogenic nature of proteins released from mitochondria was confirmed by observing changes in nuclear morphologic features and DNA fragmentation. Proteins released by 6 \u03bcM T3 contained significantly increased amounts of cytochrome <jats:italic toggle=\"yes\">c<\/jats:italic> (<jats:italic toggle=\"yes\">P<\/jats:italic> &lt; .01) and induced apoptotic changes in 67% of nuclei. In conclusion, using <jats:italic toggle=\"yes\">in vivo<\/jats:italic> and <jats:italic toggle=\"yes\">in vitro<\/jats:italic> approaches, we provide evidence that excess T3 causes liver dysfunction by inducing apoptosis, as a result of activation of a mitochondria-dependent pathway. Thus, the results of this study provide an explanation for liver dysfunction associated with hyperthyroidism. (Hepatology 2004;39:1120-1130.)<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.20085","type":"journal-article","created":{"date-parts":[[2004,3,26]],"date-time":"2004-03-26T08:02:51Z","timestamp":1080288171000},"page":"1120-1130","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":79,"title":["Severe hyperthyroidism induces mitochondria-mediated apoptosis in rat 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