Centrolobular liver fibrosis in the hypercholesterolemic rabbit.
During a study on the development of atheromatous lesions in rabbits fed a diet with a low or high cholesterol supplement, we found a moderate to pronounced centrolobular liver fibrosis. This fibrosis developed in three stages. Early after supplementation of cholesterol, we observed increased immunoreactivity of collagen types I, III, and IV, and fibronectin, around central veins and in adjacent sinusoids. In the second stage, we observed further increase of collagen and fibronectin immunoreactivity, together with the appearance of alpha-smooth muscle actin (alpha-SM actin)-positive cells and anti-rabbit macrophage monoclonal antibody (RAM 11)-positive cells. In the third stage, we observed large numbers of alpha-SM actin-positive cells, together with heavy deposition of connective tissue proteins in pericentral sinusoids, in addition to focal atrophy of parenchymal cells. By transmission electron microscopy (TEM), fat-storing cells in the pericentral regions were shown to be enlarged, to lose their lipid-droplets, and to acquire dilated rough endoplasmic reticulum corresponding to an activated phenotype. Parenchymal cells were either normal or contained numerous small lipid-droplets. They sometimes were smaller and distorted. Northern hybridization performed on total RNA of whole liver showed an increased level of collagen alpha1(I), alpha1(III), and alpha1(IV) messenger RNA (mRNA) after 24 weeks of low dietary cholesterol supplementation. These 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 fibrogenic effector cells. At present, we have no explanation why hypercholesterolemia induces phenotypic transition of fat-storing cells.
Buyssens
N
N
Division of Pharmacology, University of Antwerp-(U.I.A.), Wilrijk, Belgium.
Kockx
M M
MM
Herman
A G
AG
Lazou
J M
JM
Van den Berg
K
K
Wisse
E
E
Geerts
A
A
D000199:Actins / Q000032:analysis; D000818:Animals; D015152:Blotting, Northern; D003893:Desmin / Q000032:analysis; D005109:Extracellular Matrix / Q000737:chemistry; D006937:Hypercholesterolemia / Q000473:pathology*; D007150:Immunohistochemistry; D008106:Liver Cirrhosis, Experimental / Q000473:pathology*; D008264:Macrophages / Q000473:pathology; D008297:Male; D008854:Microscopy, Electron; D009130:Muscle, Smooth / Q000737:chemistry; D011817:Rabbits; D014746:Vimentin / Q000032:analysis
D000199:Actins; D003893:Desmin; D014746:Vimentin