Thrombospondin 1 improves hepatic steatosis in diet-induced insulin-resistant mice and is associated with hepatic fat content in humans
Thrombospondin 1 improves hepatic steatosis in diet-induced insulin-resistant mice and is associated with hepatic fat content in humans
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血小板反应蛋白 1 可改善饮食诱导的胰岛素抵抗小鼠的肝脏脂肪变性，并与人类的肝脏脂肪含量相关
DOI：
10.1016/j.ebiom.2020.102849
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发表时间：
2020-07-01
期刊：
影响因子：
11.1
通讯作者：
Gao, Xin
中科院分区：
文献类型：
--
作者：
Bai, Jinyun;Xia, Mingfeng;Gao, Xin
背景：非酒精性脂肪性肝病（NAFLD）与分泌蛋白的产生改变有关。增加对分泌蛋白的了解可以改善NAFLD的预测和治疗。在这里，我们的目的是发现新的分泌蛋白在人类与肝脂肪含量使用公正的蛋白质组学分析策略，以及如何确定的Thbs 1调节脂质代谢和肝脂肪变性。方法：NAFLD患者登记和生活方式干预治疗。对接受肝活检的患者进行入组，分析循环Thbs 1与肝脂肪变性的相关性。高脂高糖饲料喂养小鼠，并用重组Thbs 1进行治疗。从CD 36基因敲除（CD 36-/-）小鼠及其野生型同窝小鼠（对照组）分离的原代肝细胞用葡萄糖加胰岛素处理24 h，联合或不联合重组Thbs 1。结果：血清Thbs 1水平在NAFLD参与者中升高，并与肝脏脂肪变性等级呈正相关。生活方式干预后肝脏脂肪变性的改善伴随着血清Thbs 1水平的显着降低。重组人Thbs 1的药理学给药减轻饮食诱导的肥胖小鼠的肝脂肪变性。用Thbs 1蛋白或稳定过表达的Thbs 1处理引起暴露于高糖加胰岛素的原代肝细胞或HepG 2细胞中脂质积累的显著减少，表明Thbs 1以肝细胞自主的方式调节脂质代谢。从机制上讲，Thbs 1抑制SREBP-1的切割和加工，导致靶脂肪生成基因表达减少和肝脂肪变性。在暴露于高糖加胰岛素的CD 36缺陷原代肝细胞中，Thbs 1对脂肪生成和甘油三酯积累的抑制作用被消除。有趣的是，在用Thbs 1九肽模拟物ABT-526处理的原代肝细胞中观察到Thbs 1对脂质蓄积的有益作用。解释：Thbs 1是人类NAFLD的生物标志物，调节Thbs 1活性的药理学和遗传学方法可能具有治疗肝脂肪变性的治疗潜力。
Background: Nonalcoholic fatty liver disease (NAFLD) is associated with altered production of secreted proteins. Increased understanding of secreted proteins could lead to improved prediction and treatment of NAFLD. Here, we aimed to discover novel secreted proteins in humans that are associated with hepatic fat content using unbiased proteomic profiling strategy, and how the identified Thbs1 modulates lipid metabolism and hepatic steatosis.Method: NAFLD patients were enrolled and treated with lifestyle intervention. Patients who underwent liver biopsy were enrolled for analyzing the correlation between circulating Thbs1 and liver steatosis. Mice were fed on high-fat, high-sucrose diet and treated with recombinant Thbs1. Primary hepatocytes isolated from CD36 knockout (CD36-/-) mice and their wild-type littermates (controls) were treated with glucose plus insulin for 24 h together with or without recombinant Thbs1.Finding: Serum Thbs1 levels are increased in participants with NAFLD and positively associated with liver steatosis grades. Improvement of liver steatosis after lifestyle intervention was accompanied with significant reduction of serum Thbs1 levels. Pharmacological administration of recombinant human Thbs1 attenuates hepatic steatosis in diet-induced obese mice. Treatment with Thbs1 protein or stably overexpression of Thbs1 causes a significant reduction of lipid accumulation in primary hepatocytes or HepG2 cells exposed to high glucose plus insulin, suggesting that Thbs1 regulates lipid metabolism in a hepatocyte-autonomous manner. Mechanistically, Thbs1 inhibits cleavage and processing of SREBP-1, leading to a reduction of target lipogenic gene expression and hepatic steatosis. Inhibitory effects of Thbs1 on lipogenesis and triglyceride accumulation are abrogated in CD36 deficient primary hepatocytes exposed to high glucose plus insulin. Interestingly, beneficial effects of Thbs1 on lipid accumulation are observed in primary hepatocytes treated with a Thbs1 nonapeptide mimetic ABT-526.Interpretation: Thbs1 is a biomarker for NAFLD in humans, and pharmacological and genetic approaches for the modulation of Thbs1 activity may have the therapeutic potential for treating hepatic steatosis.