Abstract
ABSTRACTAt present, several procedures are used for staging liver fibrosis. However, these methods may involve clinical complications and/or present diagnostic uncertainty mainly in the early stages of the disease. Thus, this study was designed to unveil new non-invasive biomarkers of liver fibrosis in an in vivo model of fibrosis/cirrhosis induction by CCl4 inhalation by using a label-free quantitative LC-MS/MS approach. We analyzed 94 serum samples from adult Wistar rats with different degrees of liver fibrosis and 36 control rats. Firstly, serum samples from 18 CCl4-treated rats were clustered into three different groups according to the severity of hepatic and the serum proteome was characterized by label-free LC-MS/MS. Furthermore, three different pooled serum samples obtained from 16 control Wistar rats were also analyzed. Based on the proteomic data obtained, we performed a multivariate analysis which displayed three main cell signaling pathways altered in fibrosis. In cirrhosis, more biological imbalances were detected as well as multi-organ alterations. In addition, hemopexin and signal-induced proliferation-associated 1 like 1 (SIPA1L1) were selected as potential serum markers of liver fibrogenesis among all the analyzed proteins. The results were validated by ELISA in an independent group of 76 fibrotic/cirrhotic rats and 20 controls which confirmed SIPA1L1 as a potential non-invasive biomarker of liver fibrosis. In particular, SIPA1L1 showed a clear diminution in serum samples from fibrotic/cirrhotic rats and a great accuracy at identifying early fibrotic stages. In conclusion, the proteomic analysis of serum samples from CCl4-treated rats has enabled the identification of SIPA1L1 as a non-invasive marker of early liver fibrosis.
Highlights
The identification of non-invasive markers of fibroproliferative processes has been subject of considerable investigation during the last decade (Fernandez-Varo and Jimenez, 2011; Martinez et al, 2011a)
On histological examination, fibrotic lesions evolved from a weak deposition basically in the portal area to several thicker septa which resulted from more prolonged exposure to CCl4
Most of the animals exposed to CCl4 for longer periods of time developed cirrhosis, and the histological analysis displayed the formation of regenerative nodules of liver parenchyma separated by fibrotic septa (Fig. S1)
Summary
The identification of non-invasive markers of fibroproliferative processes has been subject of considerable investigation during the last decade (Fernandez-Varo and Jimenez, 2011; Martinez et al, 2011a).
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