Hepatocyte specific TIMP3 expression prevents diet dependent fatty liver disease and hepatocellular carcinoma.
Hepatocyte specific TIMP3 expression prevents diet dependent fatty liver disease and hepatocellular carcinoma.
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DOI：
10.1038/s41598-017-06439-x
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发表时间：
2017-07-27
影响因子：
4.6
通讯作者：
Menghini R
中科院分区：
文献类型：
--
作者：
Casagrande V;Mauriello A;Bischetti S;Mavilio M;Federici M;Menghini R
非酒精性脂肪性肝病(NAFLD)包括从非进行性轻度脂肪变性到肝癌的广泛情况。金属蛋白酶组织抑制因子3(TIMP3)在肥胖相关脂肪性肝病的发病机制中起一定作用，在代谢紊乱和肝癌中被沉默。我们在白蛋白启动子(AlbT3)的控制下建立了肝细胞特异性TIMP3‘功能增益’小鼠模型，并研究了它在高脂饮食(HFD)中的作用。高脂饮食16周后，TIMP3过表达显著改善糖代谢、肝脏脂肪酸氧化和胆固醇稳态。在AlbT3小鼠中观察到了CYP7A1、MDR3和MRP2基因的表达，这与较高的胆汁酸合成和输出相一致。接下来，为了评估TIMP3的关键靶点A去整合素和金属蛋白酶17(ADAM17)在这些过程中的作用，我们建立了肝细胞(A17LKO)或髓系(A17MKO)中ADAM17基因缺失的小鼠，发现只有A17LKO在HFD诱导的肝脏脂肪变性中显示出改善作用。此外，AlbT3和A17LKO均显著降低二乙基亚硝胺引发的、HFD促进的肝肿瘤形成，通过肿瘤多样性和肿瘤总面积进行评估。综上所述，这些数据表明，肝脏TIMP3可以减缓NAFLD的进展，并至少部分地通过调节ADAM17的活性来抑制肿瘤的发生。
Non-alcoholic fatty liver disease (NAFLD) encompasses a broad spectrum of conditions, ranging from non-progressive bland steatosis to hepatocarcinoma. Tissue inhibitor of metalloproteinase 3 (Timp3) has a role in the pathogenesis of fatty liver disease associated with obesity and is silenced during metabolic disorders and liver cancer. We generated an hepatocyte-specific TIMP3 ‘gain-of-function’ mouse model under the control of the Albumin promoter (AlbT3) and investigated its effects during high-fat diet (HFD). After 16 weeks of HFD, TIMP3 overexpression significantly improved glucose metabolism, hepatic fatty acid oxidation and cholesterol homeostasis. In AlbT3 mice CYP7A1, MDR3 and MRP2 gene expressions were observed, consistent with higher bile acid synthesis and export. Next, to evaluate the role of A Disintegrin and Metalloproteinase 17 (ADAM17), a crucial target of TIMP3, in these processes, we created mice deficient in Adam17 specifically in hepatocyte (A17LKO) or in myeloid lineage (A17MKO), founding that only A17LKO showed improvement in liver steatosis induced by HFD. Moreover, both, AlbT3 and A17LKO significantly reduced diethylnitrosamine-initiated, HFD-promoted hepatic tumorigenesis assessed by tumor multiplicity and total tumor area. Taken together, these data indicate that hepatic TIMP3 can slow progression of NAFLD, and tumorigenesis, at least in part, through the regulation of ADAM17 activity.
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影响因子：
5.3
作者：
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通讯作者：
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影响因子：
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DOI：
10.1161/atvbaha.111.238402
发表时间：
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