CENTROLOBULAR LIVER FIBROSIS IN THE HYPERCHOLESTEROLEMIC RABBIT

During a study on the development of atheromatous lesions in rabbits f ed a diet with a low or high cholesterol supplement, we found a modera te to pronounced centrolobular liver fibrosis. This fibrosis developed in three stages. Early after supplementation of cholesterol, we obser ved increased immunoreactivity of collagen types I, III, and IV, and f ibronectin, around central veins and in adjacent sinusoids. in the sec ond stage, we observed further increase of collagen and fibronectin im munoreactivity, together with the appearance of alpha-smooth muscle ac tin (alpha-SM actin)-positive cells and anti-rabbit macrophage monoclo nal antibody (RAM 11)-positive cells. In the third stage, we observed large numbers of alpha-SM actin-positive cells, together with heavy de position of connective tissue proteins in pericentral sinusoids, in ad dition to focal atrophy of parenchymal cells. By transmission electron microscopy (TEM), fat-storing cells in the pericentral regions were s hown to be enlarged, to lose their Lipid-droplets, and to acquire dila ted rough endoplasmic reticulum corresponding to an activated phenotyp e. Parenchymal cells were either normal or contained numerous small li pid-droplets. They sometimes were smaller and distorted. Northern hybr idization performed on total RNA of whole liver showed an increased le vel of collagen alpha 1(I), alpha 1(III), and alpha 1(IV) messenger RN A (mRNA) after 24 weeks of low dietary cholesterol supplementation. Th ese data show enhanced expression of extracellular matrix proteins. We conclude that cholesterol overload induces pericentral Liver fibrosis in rabbits. The diet clearly activates fat-storing cells to become fi brogenic effector cells. At present, we have no explanation why hyperc holesterolemia induces phenotypic transition of fat-storing cells.