Lumican, an extracellular matrix proteoglycan, is a novel requisite for hepatic fibrosis

Anuradha Krishnan, Xia Li, Winstonwhei Yang Kao, Kimberly Viker, Kim Butters, Howard Masuoka, Bruce Knudsen, Gregory Gores, Michael Charlton

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1712-1725
Number of pages14
JournalLaboratory Investigation
Volume92
Issue number12
DOIs
StatePublished - Dec 2012

Keywords

  • arbon tetrachloride
  • collagen
  • extracellular matrix
  • hepatic fibrosis
  • lumican
  • proteoglycan
  • transforming growth factor β1

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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    Krishnan, A., Li, X., Kao, W. Y., Viker, K., Butters, K., Masuoka, H., Knudsen, B., Gores, G., & Charlton, M. (2012). Lumican, an extracellular matrix proteoglycan, is a novel requisite for hepatic fibrosis. Laboratory Investigation, 92(12), 1712-1725. https://doi.org/10.1038/labinvest.2012.121