TIMP-1 is upregulated, but not essential in hepatic fibrogenesis and carcinogenesis in mice

• Main Authors: Nina D. Thiele, Jan W. Wirth, David Steins, Anja C. Koop, Harald Ittrich, Ansgar W. Lohse, Johannes Kluwe
• Format: Article
• Language: English
• Published: Nature Publishing Group 2017-04-01
• Series: Scientific Reports
• Online Access: https://doi.org/10.1038/s41598-017-00671-1

Abstract Tissue inhibitor of metalloproteinases-1 (TIMP-1) is upregulated during hepatic fibrogenesis and considered to promote fibrosis in the injured liver by inhibition of matrix metalloproteases (MMP) and degradation of extracellular matrix. Moreover, TIMP-1 displays anti-apoptotic properties, in patients with hepatocellular carcinoma (HCC) TIMP-1 serum levels are elevated and high TIMP-1 expression levels in HCC are associated with a poor prognosis. Therefore, TIMP-1 could functionally link fibrogenesis and carcinogenesis in the liver. The aim of our study was to characterize the role of TIMP-1 in hepatic fibrogenesis and carcinogenesis. Experimental hepatic fibrogenesis as well as diethylnitrosamine (DEN) -induced hepatocarcinogenesis were studied in TIMP-1-deficient mice and wild type littermates. Hepatic TIMP-1 expression was upregulated following induction of liver fibrosis by bile duct ligation (BDL) or by carbon tetrachloride (CCl4). Unexpectedly, in comparison to wild type littermates, TIMP-1-deficient mice were not protected from liver fibrosis induced by BDL or CCl4. TIMP-1 expression was significantly higher in HCC nodules than in surrounding liver tissue. However, experimental hepatic carcinogenesis was similar in TIMP-1-deficient mice and wild type littermates following DEN-treatment or combined treatment with DEN and CCl4. Therefore we concluded that TIMP-1 is not essential for hepatic fibrogenesis and carcinogenesis in mice.