Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, South Korea.
Touchstone Diabetes Center, Department of Internal Medicine, and Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, USA.
Exp Mol Med. 2020 Oct;52(10):1766-1776. doi: 10.1038/s12276-020-00520-8. Epub 2020 Oct 27.
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.
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。纤维化的肝脏的特征是细胞外基质（ECM）蛋白的病理性积累。VI 型胶原α3（Col6a3）是肝纤维化的生物标志物，其裂解形式内皮素（ETP）在脂肪组织功能障碍、胰岛素抵抗和乳腺癌发展中发挥关键作用。在这里，我们研究了 Col6a3 衍生肽 ETP 对慢性肝病（如 NASH 和肝癌）进展的影响。我们使用了一种在非酒精性脂肪性肝病倾向（肝脏特异性 SREBP1a 转基因）背景下，由强力霉素（Dox）诱导的肝脏特异性 ETP 过表达小鼠模型。为此，我们评估了肝脏中局部 ETP 表达的后果及其对肝炎症、纤维化和胰岛素抵抗的影响。ETP 在肝脏中的积累诱导了肝炎症和纤维化的发展，并伴有胰岛素抵抗。令人惊讶的是，ETP 的过表达也导致 SREBP1a 转基因背景下在 10 个月内出现肝癌。我们的数据表明，ETP 可作为 NAFLD 进展过程中的“第二次打击”，并在 NASH 和肝细胞癌（HCC）的发展中发挥重要作用。这些观察结果将 ETP 的升高水平与慢性肝病紧密联系起来。
