Tissue Inhibitor of Metalloproteinase 3 Deficiency Causes Hepatic Steatosis and Adipose Tissue Inflammation in Mice
Tissue Inhibitor of Metalloproteinase 3 Deficiency Causes Hepatic Steatosis and Adipose Tissue Inflammation in Mice
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DOI：
10.1053/j.gastro.2008.10.079
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发表时间：
2009-02-01
期刊：
影响因子：
29.4
通讯作者：
Federici, Massimo
中科院分区：
文献类型：
--
作者：
Menghini, Rossella;Menini, Stefano;Federici, Massimo
背景和目的：肥胖驱动的低度炎症会影响全身代谢功能，并可能导致胰岛素抵抗、肝脂肪变性和动脉粥样硬化。金属蛋白酶 3 (Timp3) 组织抑制剂表达的减少是胰岛素抵抗和炎症的催化剂。 Timp3 是基质金属蛋白酶、肿瘤坏死因子-α 转换酶 (TACE) 和血管内皮生长因子受体 2 的天然抑制剂，因此可能影响炎症和血管生成中涉及的信号传导过程。方法：我们评估了在环境应激（高脂肪饮食）、胰岛素抵抗遗传倾向（胰岛素受体 [Insr] 单倍体不足）和不同程度的炎症（Timp3 或 Tace 缺陷）条件下，Timp3 对小鼠炎症、组织重塑和中间代谢的影响。采用代谢测试、免疫组织化学、实时聚合酶链反应和免疫印迹来比较野生型、Insr(+/-)、Timp3(-/-)、Insr(+/-)Timp3(-/-) 和 Insr(+/-)Tace(+/-) 小鼠高脂饮食 10 周的数据。结果：与野生型、Insr(+/-)、Timp3(-/-) 和 Insr(+/-)Tace(+/-) 小鼠相比，Insr(+/-)Timp3(-/-) 小鼠表现出更高程度的脂肪和肝脏炎症。特别是，Insr(+/-)Timp3(-/-) 小鼠出现大泡性脂肪变性和严重非酒精性脂肪肝的特征，包括小叶和门静脉周围炎症、肝细胞气球样变和窦周纤维化。这些与肝脏和脂肪组织中炎症和脂肪变性标志物表达增加有关，包括细胞因子信号传导 3 和硬脂酰辅酶 A 去饱和酶 1 的抑制物。有趣的是，Insr(+/-)Tace(+/-) 小鼠具有几乎相反的表型。结论：Timp3 可能通过其对 TACE 的调节，似乎在与肥胖相关的脂肪肝疾病的发病机制中发挥作用。
Background & Aims: obesity-driven, low-grade inflammation affects systemic metabolic function and can lead to insulin resistance, hepatic steatosis, and atherosclerosis. Decreased expression of tissue inhibitor of metalloproteinase 3 (Timp3) is a catalyst for insulin resistance and inflammation. Timp3 is a natural inhibitor of matrix metalloproteinases, tumor necrosis factor-alpha-converting enzyme (TACE), and vascular endothelial growth factor receptor 2, and therefore could affect signaling processes involved in inflammation and angiogenesis. Methods: We assessed the effects of Timp3 on inflammation, tissue remodeling, and intermediary metabolism in mice, under conditions of environmental stress (high-fat diet), genetic predisposition to insulin resistance (insulin receptor [Insr] haploinsufficiency), and varying levels of inflammation (Timp3 or Tace deficiencies). Metabolic tests, immunohistochemistry, real-time polymerase chain reaction, and immunoblotting were used to compare data from wild-type, Insr(+/-), Timp3(-/-), Insr(+/-)Timp3(-/-), and Insr(+/-)Tace(+/-) mice placed on high-fat diets for 10 weeks. Results: Insr(+/-)Timp3(-/-) mice showed a higher degree of adipose and hepatic inflammation compared with wildtype, Insr(+/-), Timp3(-/-), and Insr(+/-)Tace(+/-) mice. In particular, the Insr(+/-)Timp3(-/-) mice developed macrovesicular steatosis and features of severe nonalcoholic fatty liver disease, including lobular and periportal inflammation, hepatocellular ballooning, and perisinusoidal fibrosis. These were associated with increased expression of inflammatory and steatosis markers, including suppressor of cytokine signaling 3 and stearoyl CoA desaturase 1, in both liver and adipose tissue. Interestingly, Insr(+/-)Tace(+/-) mice had a nearly opposite phenotype. Conclusions: Timp3, possibly through its regulation of TACE, appears to have a role in the pathogenesis of fatty liver disease associated with obesity.