title: Lumican, an extracellular matrix proteoglycan, is a novel requisite for hepatic fibrosis.
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.
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Krishnan
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.forename: Winstonwhei-Yang
authors.initials: WY
authors.lastname: Kao
authors.forename: Kimberly
authors.initials: K
authors.lastname: Viker
authors.forename: Kim
authors.initials: K
authors.lastname: Butters
authors.forename: Howard
authors.initials: H
authors.lastname: Masuoka
authors.forename: Bruce
authors.initials: B
authors.lastname: Knudsen
authors.forename: Gregory
authors.initials: G
authors.lastname: Gores
authors.forename: Michael
authors.initials: M
authors.lastname: Charlton
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics / Q000378:metabolism*; D003094:Collagen / Q000737:chemistry / Q000378:metabolism; D004032:Diet; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006651:Histocytochemistry; D006801:Humans; D007632:Keratan Sulfate / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000071234:Lumican; D051379:Mice; D008810:Mice, Inbred C57BL; D018709:Statistics, Nonparametric; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; C000604306:LUM protein, human; C000604307:Lum protein, mouse; D000071234:Lumican; D053773:Transforming Growth Factor beta1; D003094:Collagen; D007632:Keratan Sulfate; D002251:Carbon Tetrachloride