The role of osteopontin in d-galactosamine-induced liver injury in genetically obese mice.
Various epidemiological studies have shown that obesity increases the risk of liver disease, but the precise mechanisms through which this occurs are poorly understood. In the present study, we hypothesized that osteopontin (OPN), an extracellular matrix and proinflammatory cytokine, has an important role in making obese mice more susceptible to inflammatory liver injury. After exposure of genetically obese ob/ob and db/db mice to a single dose of d-galactosamine (GalN), the plasma liver enzyme levels, histology and expression levels of cytokines and OPN were evaluated. The ob/ob and db/db mice, which were more sensitive to GalN-induced inflammatory liver injury compared with wild-type mice, had significantly higher plasma and hepatic OPN expression levels. Increased OPN expression was mainly found in hepatocytes and inflammatory cells and was correlated with markedly up-regulated interleukin (IL)-12 and IL-18 levels. Furthermore, pretreatment with a neutralizing OPN (nOPN) antibody attenuated the GalN-induced inflammatory liver injury in ob/ob and db/db mice, which was accompanied by significantly reduced macrophages recruitment and IL-12 and IL-18 productions. Taken together, these results suggest that up-regulated OPN expression is a contributing factor to increased susceptibility of genetically obese mice to GalN-induced liver injury by promoting inflammation and modulating immune response.
Kwon
Hyo-Jung
HJ
Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Chungbuk, Korea; Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, Seoul, Korea.
Won
Young-Suk
YS
Yoon
Won-Kee
WK
Nam
Ki-Hoan
KH
Kim
Dae-Yong
DY
Kim
Hyoung-Chin
HC
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism; D005688:Galactosamine / Q000633:toxicity*; D022781:Hepatocytes / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000150:complications* / Q000235:genetics; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D016207:Cytokines; D020382:Interleukin-18; D053495:Osteopontin; D018664:Interleukin-12; D005688:Galactosamine