• biochemical markers;
  • CCl4 model;
  • Collagens;
  • connective tissue;
  • Protoglycans



We investigated nine novel biomarkers of extracellular matrix (ECM) remodelling in a rat model of liver fibrosis.


Liver fibrosis was induced in 52 male Wistar rats by inhalation of carbon tetrachloride and the level of hepatic fibrosis was assessed by Sirius red staining compared with controls. The novel serum biochemical markers assessed in the model were type I-(C1M), type III-(C3M), type IV-(C4M) and type VI-(C6M) collagen, citrullinated vimentin (VICM) and biglycan (BGM) all protein fragments generated by matrix metalloproteinases; and formation markers of type III-(P3NP), type VI (P4NP 7S) and type V (P5CP) collagen; hepatic mRNA type I collagen alpha-1 chain levels, serum potassium, sodium, osmolarity, alanine aminotransferase, lactate dehydrogenase, albumin and creatinine.


Stratification of the CCl4-treated rats according to total hepatic collagen showed that the degradation markers were significantly elevated in mild to severe fibrosis except for C6M which was also elevated in early fibrosis (< 0.05). The highest Z-scores in early and moderate fibrosis were provided by P4NP 7S and alanine aminotransferase. All nine markers of ECM remodelling were highly related to the extent of liver fibrosis induced by CCl4. The novel collagen formation marker, P4NP 7S, was reliable for the detection of early fibrosis, while the combination of the two markers, C6M and P5CP provided the best correlation with hepatic fibrosis in all fibrosis levels.


As the markers can be used for translational science, these markers may provide valuable information for the evaluation of liver fibrosis in clinical settings.