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Background information. Partial hepatectomy (70%) induces cell proliferation until the original mass of the liver is restored. In the first 24 h after partial hepatectomy, drastic changes in the metabolism of the remaining liver have been shown to occur. To evaluate changes in hepatocyte ultrastructure within the hepatic acinus during the liver regenerative process, we investigated, by light and electron microscopy observations on specimens taken 0 h, 24 h and 96 h after partial hepatectomy, the hepatocyte structure and ultrastructure in the periportal and pericentral area of the hepatic acinus, with a particular emphasis on mitochondria ultrastructure. Moreover, some biochemical events that could affect the mitochondria ultrastructure and function were investigated.Results. We found that, 24 h after partial hepatectomy, mitochondria with altered ultrastructure were preferentially localized in the periportal area. Periportal hepatocytes showed also an increase in the number of peroxisomes, free ribosomes, lysosomes and autophagosomes. Altered mitochondria showed swelling, an ultrastructural index of increased membrane permeability, a reduction in the number of cristae, and a rarefied, often vacuoled, matrix. Consistently, an increase in the mitochondrial oxidized/reduced glutathione ratio was found as well as calcium release from mitochondria in a manner inhibited by cyclosporin A. Interestingly, light and electron microscopy analysis showed that the hepatocytes in the periportal area were the cells with the major structural attributes to proliferate. At 96 h after partial hepatectomy, the preferential zonation of altered mitochondria was lost and the normal mitochondrial membrane permeability properties were restored.Conclusions. We suggest that 24 h after partial hepatectomy, a preferential zonation of altered mitochondria in the periportal hepatocytes could be involved in the changes of metabolic and functional heterogeneity of the hepatocytes within the hepatic acinus during the regenerative process.

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.