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脂肪变性，并且与人类的肝脂肪含量相关。

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. FUND: A full list of funding bodies that contributed to this study can be found in the Funding Sources section.

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能会改善 NAFLD 的预测和治疗。在这里，我们旨在使用无偏蛋白组学分析策略发现与肝脂肪含量相关的新型人类分泌蛋白，并探讨鉴定的 Thbs1 如何调节脂质代谢和肝脂肪变性。

方法：招募 NAFLD 患者并进行生活方式干预。对接受肝活检的患者进行分析，以研究循环 Thbs1 与肝脂肪变性之间的相关性。用高脂肪、高蔗糖饮食喂养小鼠，并给予重组 Thbs1 治疗。用葡萄糖加胰岛素处理 CD36 敲除（CD36-/-）小鼠及其野生型同窝仔鼠（对照）的原代肝细胞 24 h，并与或不与重组 Thbs1 一起处理。

结果：NAFLD 患者的血清 Thbs1 水平升高，并与肝脂肪变性等级呈正相关。生活方式干预后肝脂肪变性的改善伴随着血清 Thbs1 水平的显著降低。重组人 Thbs1 的药理学给药可减轻饮食诱导肥胖小鼠的肝脂肪变性。用 Thbs1 蛋白处理或稳定过表达 Thbs1 可导致暴露于高葡萄糖加胰岛素的原代肝细胞或 HepG2 细胞中脂质积累显著减少，表明 Thbs1 以肝细胞自主的方式调节脂质代谢。机制上，Thbs1 抑制 SREBP-1 的切割和加工，导致靶脂生成基因表达和肝脂肪变性减少。在暴露于高葡萄糖加胰岛素的 CD36 缺失原代肝细胞中，Thbs1 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 Thbs1 非肽模拟物 ABT-526 处理的原代肝细胞中观察到 Thbs1 对脂质积累的有益作用。

解释：Thbs1 是人非酒精性脂肪性肝病的生物标志物，调节 Thbs1 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。

资金：可在资助来源部分找到为本研究做出贡献的所有资助机构的完整列表。