Versican: a novel modulator of hepatic fibrosis

Abstract

Little is known about the deposition and turnover of proteoglycans in liver fibrosis, despite their abundance in the extracellular matrix. Versican plays diverse roles in modulating cell behavior in other fibroproliferative diseases, but remains poorly described in the liver. Hepatic fibrosis was induced by carbon tetrachloride treatment of C57BL/6 mice over 4 weeks followed by recovery over a 28-day period. Primary mouse hepatic stellate cells (HSCs) were activated in culture and versican was transiently knocked down in human (LX2) and mouse HSCs. Expression of versican, A Disintegrinlike and Metalloproteinase with Thrombospondin-1 motifs (ADAMTS)-1, -4, -5, -8, -9, -15, and -20, and markers of fibrogenesis were studied using immunohistochemistry, real-time quantitative PCR, and western blotting. Immunohistochemistry showed increased expression of versican in cirrhotic human livers and the mouse model of fibrosis. Carbon tetrachloride treatment led to significant increases in versican expression and the proteoglycanases ADAMTS-5, -9, -15, and -20, alongside TNF-α, α-smooth muscle actin (α-SMA), collagen-1, and TGF-β expression. During recovery, expression of many of these genes returned to control levels. However, expression of ADAMTS-5, -8, -9, and -15 showed delayed increases in expression at 28 days of recovery, which corresponded with decreases in versican V0 and V1 cleavage products (G1-DPEAAE 1401 and G1-DPEAAE 441 ). Activation of primary HSCs in vitro significantly increased versican, α-SMA, and collagen-1 expression. Transient knockdown of versican in HSCs led to decreases in markers of fibrogenesis and reduced cell proliferation, without inducing apoptosis. Versican expression increases during HSC activation and liver fibrosis, and proteolytic processing occurs during the resolution of fibrosis. Knockdown studies in vitro suggest a possible role of versican in modulating hepatic fibrogenesis.

C3a and suPAR drive versican V1 expression in tubular cells of focal segmental glomerulosclerosis

“…Versican is an extracellular matrix protein belonging to a family of hyaluronan-binding proteoglycans. It is a major component of the fibroproliferative matrix in hepatic fibrosis and lung fibrosis (4,21). Consistent with our findings, Einecke et al evaluated the gene expression in 105 transplanted renal biopsies and found that versican was one of the most significantly upregulated genes and predicted renal graft loss in kidney transplantation (22).…”

“…Versican is a large extracellular matrix proteoglycan that is present in a variety of human tissues. Bukong et al reported that versican expression increased during liver fibrosis (4). Rienstra et al showed that versican expression was dominant during renal fibrosis in an experimental renal transplantation rat model (5).…”

Hepatic expression profiling identifies steatosis-independent and steatosis-driven advanced fibrosis genes

“…Of these 48 genes, 35 encode extracellular proteins ( Figure 4B, highlighted in gray). Our attention was drawn to one of these, VCAN, which encodes an ECM protein recently implicated in the activation of HSCs (37) and that has also been linked to inflammation and cancer metastasis (38). VCAN mRNA expression strongly correlated with ELF score (r 2 value of 0.41) ( Figure 2) and was inducible by the profibrotic cytokine TGF-β in an EHF-dependent manner in the LX-2 HSC line ( Figure 3E).…”

“…Thus, it is tempting to speculate that selective expression of the V0 and V1 isoforms in advanced fibrosis may have some role in HCC progression. Recently, VCAN was suggested to have a role in hepatic fibrosis, with in vitro studies showing that it promotes HSC activation (37). However, its role in driving inflammation and liver fibrosis during CLD is unknown.…”

Therapeutic Benefits of Spleen Tyrosine Kinase Inhibitor Administration on Binge Drinking-Induced Alcoholic Liver Injury, Steatosis, and Inflammation in Mice

“…Relative comparison of target gene expressions made use of the comparative ΔΔCt method with no treatment control serving as baseline reference for comparisons. The 18s RNA was used gene normalisation control similar to our previous reports (Ganz et al, 2015, Bukong et al, 2016). The following primer pairs were used.…”