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首页> 外文期刊>American Journal of Physiology >Inhibition of matrix metalloproteinases increases PPAR-alpha and IL-6 and prevents dietary-induced hepatic steatosis and injury in a murine model.
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Inhibition of matrix metalloproteinases increases PPAR-alpha and IL-6 and prevents dietary-induced hepatic steatosis and injury in a murine model.

机译：在鼠模型中，基质金属蛋白酶的抑制作用会增加PPAR-α和IL-6，并防止饮食引起的肝脂肪变性和损伤。

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摘要

Steatosis is a prominent feature of nonalcoholic fatty liver disease and a potential promoter of inflammation. Injury leading to cirrhosis is partly mediated by dysregulation of matrix protein turnover. Matrix metalloproteinase (MMP) inhibitors protect mice from lethal TNF-alpha induced liver injury. We hypothesized that Marimastat, a broad-spectrum MMP and TNF-alpha converting enzyme (TACE) inhibitor, might modulate this injury through interruption of inflammatory pathways. Triglyceride and phospholipid levels (liver, serum) and fatty acid profiles were used to assess essential fatty acid status and de novo lipogenesis as mechanisms for hepatic steatosis. Mice receiving a fat-free, high-carbohydrate diet (HCD) for 19 days developed severe fatty liver infiltration, demonstrated by histology, magnetic resonance spectroscopy, and elevated liver function tests. Animals receiving HCD plus Marimastat (HCD+MAR) were comparable to control animals. Increased tissue levels of peroxisome proliferator activated receptor-alpha (PPAR-alpha), higher levels of serum IL-6, and decreased levels of serum TNF-alpha receptor II were also seen in the HCD+MAR group compared with HCD-only. In addition, there was increased phosphorylation, and likely activation, of PPAR-alpha in the HCD+MAR group. PPAR-alpha is a transcription factor involved in beta-oxidation of fatty acids, and IL-6 is a hepatoprotective cytokine. Liver triglyceride levels were higher and serum triglyceride and phospholipid levels lower with HCD-only but improved with Marimastat treatment. HCD-only and HCD+MAR groups were essential fatty acid deficient and had elevated rates of de novo lipogenesis. We therefore conclude that Marimastat reduces liver triglyceride accumulation by increasing fat oxidation and/or liver clearance of triglycerides. This may be related to increased expression and activation of PPAR-alpha or IL-6, respectively.
机译：脂肪变性是非酒精性脂肪肝疾病的突出特征，也是炎症的潜在促进因素。导致肝硬化的损伤部分由基质蛋白更新失调所介导。基质金属蛋白酶（MMP）抑制剂可保护小鼠免受TNF-α致死性肝损伤。我们假设，广谱MMP和TNF-α转换酶（TACE）抑制剂Marimastat可能通过中断炎症途径来调节这种损伤。甘油三酸酯和磷脂水平（肝脏，血清）和脂肪酸谱用于评估必需脂肪酸的状态和从头开始的脂肪生成，作为肝脂肪变性的机制。接受无脂肪，高碳水化合物饮食（HCD）喂养19天的小鼠发生了严重的脂肪肝浸润，这在组织学，磁共振波谱和肝功能测试中得到了证实。接受HCD加马立马司他（HCD + MAR）的动物与对照动物相当。与仅使用HCD相比，在HCD + MAR组中还发现过氧化物酶体增殖物激活受体-α（PPAR-alpha）的组织水平增加，血清IL-6的水平更高和血清TNF-α受体II的水平降低。另外，在HCD + MAR组中，PPAR-α的磷酸化增加，并且可能被激活。 PPAR-α是参与脂肪酸β-氧化的转录因子，IL-6是具有肝保护作用的细胞因子。仅使用HCD的患者肝脏甘油三酸酯水平较高，而血清甘油三酸酯和磷脂水平较低，但使用Marimastat治疗则可以改善。仅HCD组和HCD + MAR组是必需脂肪酸缺乏的，并且从头脂肪形成的速率升高。因此，我们得出的结论是，马立马司他通过增加脂肪氧化和/或甘油三酸酯的肝脏清除率来减少肝脏甘油三酸酯的积累。这可能分别与PPAR-α或IL-6的表达增加和激活有关。

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