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

Hepatology. 1995 Sep;22(3):780-7.


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 mumol/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 suggest that thrombin may be involved in modulating FSC proliferation and monocyte chemotaxis during human liver disease, through proteolytic activation of its receptor.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adipocytes / cytology*
  • Adipocytes / metabolism
  • Cell Division / drug effects
  • Cells, Cultured
  • Chemokine CCL2
  • Chemotactic Factors / genetics
  • Chemotactic Factors / metabolism*
  • Cytokines / metabolism
  • DNA / biosynthesis
  • Gene Expression / drug effects
  • Humans
  • Lipid Metabolism*
  • Liver / cytology*
  • Liver / metabolism
  • Liver Diseases / etiology*
  • Peptide Fragments / pharmacology
  • Receptors, Thrombin / metabolism
  • Thrombin / pharmacology*
  • Vitamin A / pharmacology


  • Chemokine CCL2
  • Chemotactic Factors
  • Cytokines
  • Peptide Fragments
  • Receptors, Thrombin
  • Vitamin A
  • thrombin receptor peptide SFLLRNP
  • DNA
  • Thrombin