Increased cytoprotective function in the liver of transgenic mice expressing osteopontin in hepatocytes

Koh, Hea Saeng; Matsui, Atsushi; Mimura, Sumie; Inao, Mie; Saitoh, Eiko; Ohno, Akihiko; Nagoshi, Sumiko; Yoshimoto, Takayuki; Mochida, Satoshi; Fujiwara, Kenji

doi:10.1016/j.hepres.2005.01.016

Cited by 8 publications

(3 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Transgenic mice that over-express OPN, after treatment with CCl 4 , demonstrate less severe liver injury and inflammation [23]. In addition, OPN expression has been found in a mouse oval cell induced model to be associated with activation of hepatic stem cells [24].…”

Section: Discussionmentioning

confidence: 99%

Plasma osteopontin in acute liver failure

Srungaram

Rule

et al. 2015

Cytokine

View full text Add to dashboard Cite

Background Osteopontin (OPN) is a novel phosphoglycoprotein expressed in Kupffer cells that plays a pivotal role in activating natural killer cells, neutrophils and macrophages. Measuring plasma OPN levels in patients with acute liver failure (ALF) might provide insights into OPN function in the setting of massive hepatocyte injury. Methods OPN levels were measured using a Quantikine® ELISA assay on plasma from 105 consecutive ALF patients enrolled by the US Acute Liver Failure Study Group, as well as controls including 40 with rheumatoid arthritis (RA) and 35 healthy subjects both before, and 1 and 3 days after undergoing spine fusion (SF) surgery as a model for acute inflammation. Results Median plasma OPN levels across all etiologies of ALF patients were elevated 10- to 30-fold: overall median 1055 ng/mL; range: 33 – 19127), when compared to healthy controls (median in pre-SF patients: 41 ng/mL; range 2.6 – 86.4). RA and SF post op patients had elevated OPN levels (37 ng/mL and 198 ng/mL respectively), well below those of the ALF patients. Median OPN levels were highest in acetaminophen (3603 ng/mL) and ischemia-related ALF (4102 ng/mL) as opposed to viral hepatitis (706 ng/mL), drug-induced liver injury (353 ng/mL) or autoimmune hepatitis (436 ng/mL), correlating with the degree of hepatocellular damage, as reflected by aminotransferase values (R value: 0.47 for AST, p < 0.001). Conclusions OPN levels appeared to correlate with degree of liver necrosis in ALF. Very high levels were associated with hyperacute injury and good outcomes. Whether OPN exerts a protective effect in limiting disease progression in this setting remains uncertain.

show abstract

Section: Discussionmentioning

confidence: 99%

Plasma osteopontin in acute liver failure

Srungaram

Rule

et al. 2015

Cytokine

View full text Add to dashboard Cite

show abstract

“…28 In contrast, liver necrosis and ALT levels were lower in the transgenic mice overexpressing OPN in hepatocytes when treated with carbon tetrachloride. 29 …”

Section: Discussionmentioning

confidence: 99%

Osteopontin deficiency aggravates hepatic injury induced by ischemia–reperfusion in mice

et al. 2014

View full text Add to dashboard Cite

Osteopontin (OPN) is a multifunctional protein involved in hepatic steatosis, inflammation, fibrosis and cancer progression. However, its role in hepatic injury induced by ischemia–reperfusion (I–R) has not yet been investigated. We show here that hepatic warm ischemia for 45 min followed by reperfusion for 4 h induced the upregulation of the hepatic and systemic level of OPN in mice. Plasma aspartate aminotransferase and alanine aminotransferase levels were strongly increased in Opn−/− mice compared with wild-type (Wt) mice after I–R, and histological analysis of the liver revealed a significantly higher incidence of necrosis of hepatocytes. In addition, the expression levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNFα), interleukin 6 (IL6) and interferon-γ were strongly upregulated in Opn−/− mice versus Wt mice after I–R. One explanation for these responses could be the vulnerability of the OPN-deficient hepatocyte. Indeed, the downregulation of OPN in primary and AML12 hepatocytes decreased cell viability in the basal state and sensitized AML12 hepatocytes to cell death induced by oxygen–glucose deprivation and TNFα. Further, the downregulation of OPN in AML12 hepatocytes caused a strong decrease in the expression of anti-apoptotic Bcl2 and in the ATP level. The hepatic expression of Bcl2 also decreased in Opn−/− mice versus Wt mice livers after I–R. Another explanation could be the regulation of the macrophage activity by OPN. In RAW macrophages, the downregulation of OPN enhanced iNOS expression in the basal state and sensitized macrophages to inflammatory signals, as evaluated by the upregulation of iNOS, TNFα and IL6 in response to lipopolysaccharide. In conclusion, OPN partially protects from hepatic injury and inflammation induced in this experimental model of liver I–R. This could be due to its ability to partially prevent death of hepatocytes and to limit the production of toxic iNOS-derived NO by macrophages.

show abstract

“…We have demonstrated in this model that osteopontin (OPN) plays an important role in the progression from steatosis to steatohepatitis and liver fibrosis (30). OPN is synthesized and secreted by immune cells as well as epithelial, endothelial, and smooth muscle cells (19) and has been shown to function as a Th1 cytokine in the pathogenesis of fibroinflammatory diseases in various organ systems including the liver (1,8,9,12,13,16,21,24,37). We have shown that hepatocytes in culture synthesize and secrete OPN and that its expression is upregulated by TNF-␣, transforming growth factor (TGF)-␤, and leptin (30).…”

mentioning

confidence: 99%