Lee Jin-Hyung, Banerjee Atrayee, Ueno Yoshi, Ramaiah Shashi K
Department of Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas 77843-4467, USA.
Toxicol Sci. 2008 Nov;106(1):290-9. doi: 10.1093/toxsci/kfn165. Epub 2008 Aug 14.
Osteopontin (OPN) up-regulation is known to mediate hepatic inflammation in a rodent model of alcoholic liver disease (ALD) and alcohol ingestion is reported to inhibit hepatic peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activity leading to hepatic steatosis and inflammation. Therefore, the objective of this study was to investigate the potential relationship between the anti-inflammatory PPAR-alpha and proinflammatory OPN in rats and mice livers, and cell cultures of hepatocytes and biliary epithelium. Experiments were designed to evaluate the influence of ethanol (EtOH), lipopolysaccharide (LPS), and acetaldehyde (ACA) on OPN and PPAR-alpha expression levels in vivo (rats and mice) and in vitro (hepatocytes and biliary epithelium). Adult Sprague-Dawley rats and C57BL6 mice were fed EtOH-containing Lieber-DeCarli liquid diet for 6 weeks and injected with a single dose of LPS. A combination of EtOH and LPS treated rats and mice showed significant induction of hepatic OPN expression compared with the controls. Similarly, cells exposed to physiological doses of EtOH, LPS, a combination of EtOH and LPS, and ACA resulted in increased OPN protein and mRNA expression. Rats and mice in ALD model and cells treated with EtOH and ACA showed downregulation of PPAR-alpha mRNA. Also, DNA binding activity of PPAR-alpha to PPAR response element was significantly reduced following treatment. Overexpression of PPAR-alpha rescued the reduced PPAR-alpha activity and PPAR-alpha agonist, bezafibrate, elevated PPAR-alpha activity after treatment of EtOH, LPS, and ACA when cells were exposed by bezafibrate. To further delineate the potential relationship between OPN and PPAR-alpha, OPN(-/-) mice showed no change of PPAR-alpha mRNA level although wild-type mice showed downregulation of PPAR-alpha mRNA after EtOH treatment. In conclusion, the current study suggests that OPN is induced by EtOH and its metabolite ACA and opposite relationship likely exist between PPAR-alpha and OPN expression within the liver during ALD.
已知骨桥蛋白（OPN）上调介导酒精性肝病（ALD）啮齿动物模型中的肝脏炎症，并且据报道酒精摄入会抑制肝脏过氧化物酶体增殖物激活受体α（PPAR-α）活性，导致肝脏脂肪变性和炎症。因此，本研究的目的是探讨抗炎性PPAR-α与促炎性OPN在大鼠和小鼠肝脏以及肝细胞和胆管上皮细胞培养物中的潜在关系。实验旨在评估乙醇（EtOH）、脂多糖（LPS）和乙醛（ACA）对体内（大鼠和小鼠）和体外（肝细胞和胆管上皮细胞）OPN和PPAR-α表达水平的影响。成年Sprague-Dawley大鼠和C57BL6小鼠喂食含EtOH的Lieber-DeCarli液体饮食6周，并注射单剂量LPS。与对照组相比，EtOH和LPS联合处理的大鼠和小鼠肝脏OPN表达显著诱导。同样，暴露于生理剂量EtOH、LPS、EtOH和LPS组合以及ACA的细胞导致OPN蛋白和mRNA表达增加。ALD模型中的大鼠和小鼠以及用EtOH和ACA处理的细胞显示PPAR-α mRNA下调。此外，处理后PPAR-α与PPAR反应元件的DNA结合活性显著降低。PPAR-α过表达挽救了降低的PPAR-α活性，并且当细胞用苯扎贝特处理时，PPAR-α激动剂苯扎贝特在EtOH、LPS和ACA处理后提高了PPAR-α活性。为了进一步阐明OPN与PPAR-α之间的潜在关系，OPN基因敲除（-/-）小鼠的PPAR-α mRNA水平没有变化，尽管野生型小鼠在EtOH处理后PPAR-α mRNA下调。总之，当前研究表明EtOH及其代谢产物ACA诱导OPN，并且在ALD期间肝脏内PPAR-α与OPN表达之间可能存在相反的关系。
