Osteopontin binding to lipopolysaccharide lowers tumor necrosis factor-α and prevents early alcohol-induced liver injury in mice.
Osteopontin binding to lipopolysaccharide lowers tumor necrosis factor-α and prevents early alcohol-induced liver injury in mice.
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DOI：
10.1002/hep.26931
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发表时间：
2014-04
期刊：
影响因子：
13.5
通讯作者：
Nieto, Natalia
中科院分区：
文献类型：
--
作者：
Ge, Xiaodong;Leung, Tung-Ming;Arriazu, Elena;Lu, Yongke;Urtasun, Raquel;Christensen, Brian;Fiel, Maria Isabel;Mochida, Satoshi;Sorensen, Esben S.;Nieto, Natalia
尽管骨桥蛋白（OPN）在酒精性肝病患者中被诱导，但其在酒精性肝病（ALD）病理生理学中的作用仍不清楚。肠内脂多糖（LPS）移位增加是ALD发病的关键，因为它促进巨噬细胞浸润和活化、肿瘤坏死因子-α（TNFα）产生和肝损伤。由于OPN对肠粘膜具有保护作用，我们推测，增强OPN在肝脏中的表达，从而在血液和/或肠道中的表达可以保护早期酒精诱导的肝损伤。野生型（WT）、OPN敲除（Opn−/−）和肝细胞中过表达OPN的转基因小鼠（OpnHEP Tg）长期喂食对照或乙醇Lieber-DeCarli饮食。在OpnHEP Tg小鼠中，乙醇增加肝脏、血浆、胆汁和粪便OPN的程度高于WT小鼠。在乙醇处理的OpnHEP Tg小鼠中，脂肪变性较少，如通过降低的肝体重比、肝甘油三酯、脂肪变性评分、油红-O染色和脂质过氧化所示。ALT活性降低、肝细胞气球样变性、LPS水平、炎症评分以及巨噬细胞和TNFα+细胞数量减少证明炎症和肝损伤也较少。为了确定OPN是否可以限制LPS的可用性及其在肝脏中的毒性作用，进行了结合研究。OPN对LPS具有亲和力，其结合阻止了巨噬细胞活化、活性氧和氮物质的产生以及TNFα的产生。用牛奶OPN（m-OPN）治疗在体内阻断LPS移位并保护早期酒精诱导的肝损伤。肝脏中OPN的自然诱导加强制过表达和m-OPN治疗通过阻断肝脏中肠源性LPS和TNFα作用来保护早期酒精诱导的肝损伤。
Although osteopontin (OPN) is induced in alcoholic patients, its role in the pathophysiology of alcoholic liver disease (ALD) remains unclear. Increased translocation of lipopolysaccharide (LPS) from the gut is key for the onset of ALD since it promotes macrophage infiltration and activation, tumor necrosis factor-α (TNFα) production and liver injury. Since OPN is protective for the intestinal mucosa, we postulated that enhancing OPN expression in the liver and consequently in the blood and/or in the gut could protect from early alcohol-induced liver injury. Wild-type (WT), OPN knockout (Opn−/−) and transgenic mice overexpressing OPN in hepatocytes (OpnHEP Tg) were chronically fed either the control or the ethanol Lieber-DeCarli diet. Ethanol increased hepatic, plasma, biliary and fecal OPN more in OpnHEP Tg than in WT mice. Steatosis was lesser in ethanol-treated OpnHEP Tg mice as shown by decreased liver-to-body weight ratio, hepatic triglycerides, the steatosis score, oil red-O staining and lipid peroxidation. There was also less inflammation and liver injury as demonstrated by lower ALT activity, hepatocyte ballooning degeneration, LPS levels, the inflammation score and the number of macrophages and TNFα+ cells. To establish if OPN could limit LPS availability and its noxious effects in the liver, binding studies were performed. OPN showed affinity for LPS and the binding prevented macrophage activation, reactive oxygen and nitrogen species generation and TNFα production. Treatment with milk OPN (m-OPN) blocked LPS translocation in vivo and protected from early alcohol-induced liver injury. Natural induction plus forced overexpression of OPN in the liver and treatment with m-OPN protect from early alcohol-induced liver injury by blocking the gut-derived LPS and TNFα effects in the liver.
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