A structural analysis of gap and tight junctions in the rat liver during a dietary treatment that induces oval cell proliferation.

The authors have investigated early changes in liver cell gap and tight junctions that occur when rats are fed a carcinogenic diet. Animals were fed a choline-deficient diet that contained 0.1% ethionine (CDE) for periods up to 6 weeks. Short-term feeding of this diet results in the rapid proliferation of so-called "oval cells" within the liver, which is reversible upon returning the rats to a normal diet. Livers from animals fed the diet were removed at various times during feeding and during recovery from the diet and were analyzed by light and electron microscopy. The freeze-fracture technique was used to produce extended views of the internal structure of liver cell membranes at each stage under study. The characteristic junctional complex surrounding canalicular regions in normal liver disappears after only 2 weeks of the CDE regimen. Gap junctions were not found after 4 weeks of the diet, and tight junctions became increasingly disorganized. Tight junction elements were observed, however, between hepatocytes and oval cells, which indicated that these two cell types do interact directly. Changes occur in the structural complexity of tight junction elements between hepatocytes and between hepatocytes and oval cells. Recovery from the CDE diet results in a rapid increase in junctional complexity, and the large gap junction plaques characteristic of normal liver are visible within 2 weeks after cessation of the CDE regimen. These and other observations demonstrate that reversible alterations in hepatocyte gap and tight junctions occur as a result of administration of a diet that induces oval cell proliferation. The relationship of these changes to those that have been reported during other processes of cell proliferation are discussed.