Tumor necrosis factor α-converting enzyme inhibition reverses hepatic steatosis and improves insulin sensitivity markers and surgical outcome in mice.
Tumor necrosis factor α-converting enzyme inhibition reverses hepatic steatosis and improves insulin sensitivity markers and surgical outcome in mice.
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肿瘤坏死因子α转化酶抑制作用逆转肝脂肪变性，并改善小鼠的胰岛素敏感性标志物和手术结果。
DOI：
10.1371/journal.pone.0025587
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Puder M
中科院分区：
文献类型：
--
作者：
de Meijer VE;Le HD;Meisel JA;Sharma AK;Popov Y;Puder M
肝脂肪变性是主要肝切除术后并发症的一个确定的危险因素。然而，缺乏在手术前逆转脂肪变性的药理学选择。我们假设，使用药理学肿瘤坏死因子-α转换酶（TACE）抑制剂Marimastat治疗可逆转已建立的脂肪变性，从而改善肝切除术后的结局。对C57 BL/6雄性小鼠饲喂高脂肪饲料9周，以建立肥胖、肝脂肪变性和胰岛素抵抗，并额外给予Marimastat或溶媒2周或4周。用Marimastat处理瘦素缺陷、高胰岛素血症ob/ob小鼠4周。通过磁共振波谱定量肝脏脂肪变性，并通过组织学证实。两周后，Marimastat处理的动物显著改善了胰岛素敏感性和肝脏组织学的替代标志物，脂肪变性降低了66%（P = 0.010）。 这些发现在ob/ob小鼠中得到证实。与脂肪酸合成相关的转录物在Marimastat处理的动物中显著下调。在用Marimastat或媒介物预处理两周后，对高脂肪喂养的C57 BL/6小鼠进行三分之二肝切除术。与对照组相比，通过血清天冬氨酸转氨酶水平和丙氨酸转氨酶水平定量的术后肝损伤分别显著降低了57%（P = 0.020）和44%（P =0.032）。 用TACE抑制剂Marimastat治疗改善了胰岛素敏感性的替代标志物，并逆转了饮食诱导的肥胖和瘦素缺乏的小鼠模型中的脂肪变性，从而减轻了肝切除术后的术后损伤。这可能表明脂肪肝患者的潜在治疗作用;特别是那些需要接受肝切除术的患者。
Hepatic steatosis is an established risk factor for complications following major hepatic resection. Pharmacological options to reverse steatosis prior to surgery, however, are lacking. We hypothesized that treatment with the pharmacologic tumor necrosis factor-α converting enzyme (TACE)-inhibitor Marimastat would reverse established steatosis, leading to improved outcome following hepatectomy. C57BL/6 male mice were fed a high fat diet for 9 weeks to establish obesity, hepatic steatosis and insulin resistance, and were administered either Marimastat or vehicle for an additional 2 or 4 weeks. Leptin deficient, hyperinsulinemic ob/ob mice were treated with Marimastat for 4 weeks. Hepatic steatosis was quantified by magnetic resonance spectroscopy and confirmed by histology. After two weeks, Marimastat-treated animals significantly improved surrogate markers for insulin sensitivity and liver histology, and experienced a 66% decrease in steatosis (P = 0.010). These findings were confirmed in ob/ob mice. Transcripts related to fatty acid synthesis were significantly downregulated in Marimastat-treated animals. Following pre-treatment with Marimastat or vehicle for two weeks, high fat fed C57BL/6 mice were subjected to two-thirds hepatectomy. Post-operative liver injury as quantified by serum aspartate aminotransferase levels and alanine aminotransferase levels was significantly decreased by 57% (P = 0.020) and 44% (P = 0.032) respectively, compared to controls. Treatment with the TACE-inhibitor Marimastat improved surrogate markers for insulin sensitivity and reversed steatosis in mouse models of diet-induced obesity and leptin deficiency, thereby attenuating post-operative injury following hepatectomy. This may suggest a potential therapeutic role in patients with fatty liver disease; especially those who need to undergo hepatic resection.
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