The impact of endotrophin on the progression of chronic liver disease.
The impact of endotrophin on the progression of chronic liver disease.
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DOI：
10.1038/s12276-020-00520-8
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发表时间：
2020-10
影响因子：
12.8
通讯作者：
Scherer PE
中科院分区：
文献类型：
--
作者：
Kim M;Lee C;Seo DY;Lee H;Horton JD;Park J;Scherer PE
非酒精性脂肪性肝病（NAFLD）是最常见的肝脏疾病，可导致多种并发症，包括非酒精性脂肪性肝炎（NASH）、肝硬化和肝细胞癌。纤维化肝的特点是细胞外基质（ECM）蛋白的病理性积累。VI型胶原α 3 （Col6a3）是肝纤维化的生物标志物，其裂解形式内啡肽（ETP）在脂肪组织功能障碍、胰岛素抵抗和乳腺癌发展中起着关键作用。在这里，我们研究了col6a3衍生肽ETP对慢性肝脏疾病（如NASH和肝癌）进展的影响。我们使用了多西环素（Dox）诱导的肝脏特异性etp过表达小鼠模型，该模型具有nafld易发（肝脏特异性SREBP1a转基因）背景。为此，我们评估了肝脏中局部ETP表达的后果及其对肝脏炎症、纤维化和胰岛素抵抗的影响。肝脏中ETP的积累诱导肝脏炎症和纤维化的发展，并伴有相关的胰岛素抵抗。令人惊讶的是，在SREBP1a转基因背景下，ETP过表达也会导致肝癌在10个月内出现。我们的数据显示，在NAFLD的进展过程中，ETP可以作为“第二次打击”，并在NASH和肝细胞癌（HCC）的发展中发挥重要作用。这些观察结果坚定地将ETP水平升高与慢性肝病联系起来。肝脏中胶原源性裂解片段的局部积聚在加速小鼠组织瘢痕和肝癌的发展中起着关键作用。由美国达拉斯德克萨斯大学西南医学中心的Philipp Scherer和韩国蔚山国家科学技术研究所的Jiyoung Park领导的研究小组利用脂肪性肝病的转基因小鼠模型表明，肝脏特异性积累的胶原蛋白片段（称为内啡肽）导致炎症和纤维化途径的激活。这些小鼠随后会出现代谢功能障碍、胰岛素抵抗，随着时间的推移，还会出现肝脏癌结节。研究结果表明，当内啡肽在已经含有大量脂肪的肝组织中积聚时，可能会破坏正常的肝脏生理机能，加速器官损伤。
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and can lead to multiple complications, including non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma. The fibrotic liver is characterized by the pathological accumulation of extracellular matrix (ECM) proteins. Type VI collagen alpha3 (Col6a3) is a biomarker of hepatic fibrosis, and its cleaved form, endotrophin (ETP), plays a critical role in adipose tissue dysfunction, insulin resistance, and breast cancer development. Here, we studied the effects of the Col6a3-derived peptide ETP on the progression of chronic liver diseases, such as NASH and liver cancer. We used a doxycycline (Dox)-inducible liver-specific ETP-overexpressing mouse model on a NAFLD-prone (liver-specific SREBP1a transgenic) background. For this, we evaluated the consequences of local ETP expression in the liver and its effect on hepatic inflammation, fibrosis, and insulin resistance. Accumulation of ETP in the liver induced hepatic inflammation and the development of fibrosis with associated insulin resistance. Surprisingly, ETP overexpression also led to the emergence of liver cancer within 10 months in the SREBP1a transgenic background. Our data revealed that ETP can act as a “second hit” during the progression of NAFLD and can play an important role in the development of NASH and hepatocellular carcinoma (HCC). These observations firmly link elevated levels of ETP to chronic liver disease. Localized buildup in the liver of a collagen-derived cleavage fragment plays a critical role in accelerating the development of tissue scarring and liver cancer in mice. Using a transgenic mouse model of fatty liver disease, a team led by Philipp Scherer from the University of Texas Southwestern Medical Center, Dallas, USA, and Jiyoung Park of Ulsan National Institute of Science and Technology, South Korea, showed that liver-specific accumulation of a collagen fragment known as endotrophin leads to activation of inflammatory and fibrotic pathways. The mice subsequently develop metabolic dysfunction, insulin resistance and, with time, cancerous nodules in the liver. The findings suggest that endotrophin accumulation, when it occurs in liver tissue that already contains large depositions of fat, can overwhelm normal liver physiology and accelerate organ damage.
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4.2
作者：
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通讯作者：
Largaespada, David A.
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