Sahai Atul, Malladi Padmini, Melin-Aldana Hector, Green Richard M, Whitington Peter F
Department of Pediatrics, Children's Memorial Institute for Education and Research, Northwestern University, 2300 Children's Plaza, box 212, Chicago, IL 60614, USA.
Am J Physiol Gastrointest Liver Physiol. 2004 Jul;287(1):G264-73. doi: 10.1152/ajpgi.00002.2004. Epub 2004 Mar 25.
The pathogenesis of nonalcoholic steatohepatitis (NASH) is poorly defined. Feeding mice a diet deficient in methionine and choline (MCD diet) induces experimental NASH. Osteopontin (OPN) is a Th1 cytokine that plays an important role in several fibroinflammatory diseases. We examined the role of OPN in the development of experimental NASH. A/J mice were fed MCD or control diet for up to 12 wk, and serum alanine aminotransferase (ALT), liver histology, oxidative stress, and the expressions of OPN, TNF-alpha, and collagen I were assessed at various time points. MCD diet-fed mice developed hepatic steatosis starting after 1 wk and inflammation by 2 wk; serum ALT increased from day 3. Hepatic collagen I mRNA expression increased during 1-4 wk, and fibrosis appeared at 8 wk. OPN protein expression was markedly increased on day 1 of MCD diet and persisted up to 8 wk, whereas OPN mRNA expression was increased at week 4. TNF-alpha expression was increased from day 3 to 2 wk, and evidence of oxidative stress did not appear until 8 wk. Increased expression of OPN was predominantly localized in hepatocytes. Hepatocytes in culture also produced OPN, which was stimulated by transforming growth factor-beta and TNF-alpha. Moreover, MCD diet-induced increases in serum ALT levels, hepatic inflammation, and fibrosis were markedly reduced in OPN(-/-) mice when compared with OPN(+/+) mice. In conclusion, our results demonstrate an upregulation of OPN expression early in the development of steatohepatitis and suggest an important role for OPN in signaling the onset of liver injury and fibrosis in experimental NASH.
非酒精性脂肪性肝炎（NASH）的发病机制尚不清楚。给小鼠喂食缺乏蛋氨酸和胆碱的饮食（MCD饮食）可诱发实验性NASH。骨桥蛋白（OPN）是一种Th1细胞因子，在几种纤维炎症性疾病中起重要作用。我们研究了OPN在实验性NASH发展中的作用。将A/J小鼠喂食MCD或对照饮食长达12周，并在不同时间点评估血清丙氨酸转氨酶（ALT）、肝脏组织学、氧化应激以及OPN、肿瘤坏死因子-α（TNF-α）和I型胶原的表达。喂食MCD饮食的小鼠在1周后开始出现肝脂肪变性，2周时出现炎症；血清ALT从第3天开始升高。肝脏I型胶原mRNA表达在1至4周期间增加，8周时出现纤维化。OPN蛋白表达在MCD饮食第1天显著增加，并持续至8周，而OPN mRNA表达在第4周增加。TNF-α表达从第3天至2周增加，氧化应激证据直到8周才出现。OPN表达增加主要定位于肝细胞。培养的肝细胞也产生OPN，其受到转化生长因子-β和TNF-α的刺激。此外，与OPN（+/+）小鼠相比，OPN（-/-）小鼠中MCD饮食诱导的血清ALT水平升高、肝脏炎症和纤维化明显减轻。总之，我们的结果表明在脂肪性肝炎发展早期OPN表达上调，并提示OPN在实验性NASH中肝脏损伤和纤维化起始信号传导中起重要作用。
