Thrombin stimulates proliferation of liver fat-storing cells and expression of monocyte chemotactic protein-1: Potential role in liver injury

Authors

  • Dr Fabio Marra,

    1. Department of Medicine, University of Texas Health Science Center at San Antonio, and Audie L. Murphy Memorial Veterans Administration Hospital, San Antonio, TX
    Current affiliation:
    1. Istituto di Medicina Interna, Viale Morgagni, 85, I-50134 Florence, Italy
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  • Giuseppe Grandaliano,

    1. Department of Medicine, University of Texas Health Science Center at San Antonio, and Audie L. Murphy Memorial Veterans Administration Hospital, San Antonio, TX
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  • Anthony J. Valente,

    1. Department of Pathology, University of Texas Health Science Center at San Antonio, and Audie L. Murphy Memorial Veterans Administration Hospital, San Antonio, TX
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  • Hanna E. Abboud MD

    Corresponding author
    1. Department of Medicine, University of Texas Health Science Center at San Antonio, and Audie L. Murphy Memorial Veterans Administration Hospital, San Antonio, TX
    • Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78284
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Abstract

Liver fat-storing cells (FSC) proliferate and secrete extracellular matrix in experimental models of liver injury. In this study, we determined if thrombin, a serine protease produced during acute and chronic tissue injury, modulates the functions of FSC. Thrombin stimulated DNA synthesis and proliferation of FSC, as assessed by [3H]-thymidine incorporation assay and measurement of cell number, respectively. Thrombin also increased the secretion of monocyte chemotactic protein-1 (MCP-1) in a time-and dose-dependent fashion. The effect of thrombin on both DNA synthesis and MCP-1 secretion was neutralized by pretreatment of thrombin with hirudin. The increased MCP-1 secretion was associated with increased steady-state levels of MCP-1 messenger RNA. Pretreatment of FSC with 5 μmol/L retinol for 48 hours inhibited the mitogenic effects of thrombin but not the induction of MCP-1 secretion. FSC express specific transcripts encoding for the human thrombin receptor, as shown by Northern blot analysis of poly (A)+ RNA. Proteolytic activation of the thrombin receptor results in the formation of a new N-terminus that functions as a tethered ligand. We studied the effects of a thrombin receptor activating peptide (TRAP) corresponding to the newly formed N-terminus, on FSC. TRAP mimicked the effects of thrombin on [3H]-thymidine incorporation, MCP-1 secretion, and MCP-1 gene expression. This study suggests that thrombin may be involved in modulating FSC proliferation and monocyte chemotaxis during human liver disease, through proteolytic activation of its receptor. (Hepatology 1995; 22:780–787.)

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