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Thyroid Hormone Treatment of Hypothyroid Rats Restores the Regenerative Capacity and the Mitochondrial Membrane Permeability Properties of the Liver after Partial Hepatectomy

Institute of Biomembranes and Bioenergetics, National Research Council (L.M., E.M., M.G.); and Department of Medical Biochemistry and Biology, University of Bari (F.C.), I-70126 Bari, Italy

Address all correspondence and requests for reprints to: Dr. Margherita Greco, Institute of Biomembranes and Bioenergetics, National Research Council, Via Amendola 165/A, I-70126 Bari, Italy. E-mail: csmmmg14{at}area.area.ba.cnr.it.

We have investigated the effect of thyroid hormone on recovery of liver mass and on the mitochondrial membrane permeability properties during rat liver regeneration after 70% partial hepatectomy (PH). In the euthyroid state, liver weight starts to recover 24 h after PH and is completely restored 96 h after PH. Cyclosporin A (CsA)-sensitive mitochondrial permeability transition (MPT) occurs 24 h after PH, and it has been suggested to act in the signaling mechanism for hepatocyte proliferation. In this study we show that hypothyroidism delays recovery of the liver mass, being only 50% of the initial weight 96 h after PH, and alters the duration and mode of MPT occurrence, first inducing a CsA-insensitive swelling 24 h after PH, followed by a CsA-sensitive swelling 96 h after PH. The occurrence of both CsA-sensitive and -insensitive swelling is shown to be associated with an increase in mitochondrial calcium content. Concurrent with mitochondrial swelling, external release of matrix proteins from mitochondria, such as aspartate aminotransferase and malate dehydrogenase, is shown to be CsA insensitive 24 h after PH and CsA sensitive 96 h after PH. After thyroid hormone administration to hypothyroid rats, the liver regenerative capacity is restored, and the duration and mode of MPT occurrence as well as changes in mitochondrial calcium content become similar to those observed in the euthyroid condition. The results of the present study suggest the involvement of a mitochondria-mediated pathway in regulation of the liver regenerative process by thyroid hormone.

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