Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model
Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model
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DOI：
10.1152/ajpgi.00002.2004
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发表时间：
2004-07-01
影响因子：
4.5
通讯作者：
Whitington, PF
中科院分区：
文献类型：
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作者：
Sahai, A;Malladi, P;Whitington, PF
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）会诱发实验性 NASH。骨桥蛋白 (OPN) 是一种 Th1 细胞因子，在多种纤维炎症疾病中发挥重要作用。我们研究了 OPN 在实验性 NASH 发展中的作用。 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氨基转移酶 (ALT)、肝脏组织学、氧化应激以及 OPN、TNF-α 和胶原蛋白 I 的表达。 MCD饮食喂养的小鼠在1周后开始出现肝脂肪变性，并在2周后出现炎症；第3天起血清ALT升高。第1-4周肝I型胶原mRNA表达增加，第8周出现纤维化。 OPN 蛋白表达在 MCD 饮食的第 1 天显着增加，并持续长达 8 周，而 OPN mRNA 表达在第 4 周增加。TNF-α 表达从第 3 天到第 2 周增加，直到第 8 周才出现氧化应激的证据。 OPN 表达增加主要集中在肝细胞中。培养的肝细胞也产生 OPN，它受到转化生长因子-β 和 TNF-α 的刺激。此外，与 OPN+/+ 小鼠相比，MCD 饮食引起的 OPN-/- 小鼠血清 ALT 水平升高、肝脏炎症和纤维化显着减少。总之，我们的结果表明 OPN 表达在脂肪性肝炎发展的早期上调，并表明 OPN 在实验性 NASH 中肝损伤和纤维化发生的信号中发挥着重要作用。
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.