Lumican, an extracellular matrix
proteoglycan was previously shown to be upregulated with increasing severity of
nonalcoholic steatohepatitis (NASH). Although
lumican is involved in
collagen fibrillogenesis in extra-hepatic tissues, little is known about the role of
lumican in hepatic disease. We therefore determined
lumican expression in etiologies other than clinical NASH. Our results indicated that
lumican is upregulated in clinical samples of hepatitis C virus
infection, in experimental rodent models of chronic and acute liver injury and could additionally be induced in vitro in response to the pro-fibrotic
cytokine transforming growth factor β1 (TGFβ1) and to lipotoxic
palmitic acid. Together, these results suggested a role for
lumican in hepatic
fibrosis. To investigate the functional role of
lumican in hepatic
fibrosis,
lumican null (Null) and wild-type (WT) littermates were administered
carbon tetrachloride intra-peritoneally. Serum and liver tissue were analyzed for indices of liver injury,
fibrosis, matrix turnover, and proliferation. Hepatic
fibrosis was greatly reduced in null animals (P<0.05). Paradoxically, gene expression of
fibrosis-related genes such as TGFβ1 and
collagen 1 was numerically higher in null animals though statistically insignificant from WT animals. On the other hand, α smooth muscle actin expression (α-SMA), a marker for activated fibroblasts, the main contributors of
collagen production was significantly higher (P<0.05) in null animals as compared with WT littermates. Among the matrix
metalloproteases (
MMP), MMP13 was significantly increased (P<0.05) in null animals. Ultra-structural imaging indicated differences in the organization and spatial distribution of hepatic
collagen fibrils of null and WT mice. Cell proliferation was significantly increased (P<0.05) in null animals. We conclude that
lumican is a prerequisite for hepatic
fibrosis. The protective effect of
lumican deficiency in hepatic
fibrosis appears to be downstream of
collagen production and mediated through the combined effects of impaired
collagen fibrillogenesis, increased matrix turnover, and an enhanced proliferative response.