Institute of Cerebrovascular Diseases, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
Medical College, Qingdao University, Qingdao, 266071, China.
Mol Cell Biochem. 2021 Jun;476(6):2527-2538. doi: 10.1007/s11010-020-03990-6. Epub 2021 Feb 26.
Liver fibrosis, with the characterization of progressive accumulation of extracellular matrix (ECM), is the common pathologic feature in the process of chronic liver disease. Hepatic stellate cells (HSCs) which are activated and differentiate into proliferative and contractile myofibroblasts are recognized as the main drivers of fibrosis. Obesity-related adipocytokine dysregulation is known to accelerate liver fibrosis progression, but the direct fibrogenic effect of mature adipocytes on HSCs has been rarely reported. Therefore, the purpose of this study was to explore the fibrogenic effect of adipocyte 3T3-L1 cells on hepatic stellate LX-2 cells. The results showed that incubating LX-2 cells with the supernatant of 3T3-L1 adipocytes triggered the expression of ECM related proteins, such as α-smooth muscle actin (α-SMA), type I collagen (CO-I), and activated TGF β/Smad2/3 signaling pathway in LX-2 cells. In addition, 3T3-L1 cells inhibited insulin sensitivity, activated endoplasmic reticulum stress and autophagy to promote the development of fibrosis. These results supported the notion that mature adipocytes can directly activate hepatic stellate cells, and the establishment of an in vitro model of adipocytes on HSCs provides an insight into screening of drugs for liver diseases, such as nonalcoholic fatty liver disease.
肝纤维化的特征是细胞外基质（ECM）的进行性积累，是慢性肝病过程中的共同病理特征。肝星状细胞（HSCs）被激活并分化为增殖和收缩的肌成纤维细胞，被认为是纤维化的主要驱动因素。肥胖相关的脂肪细胞因子失调被认为会加速肝纤维化的进展，但成熟脂肪细胞对 HSCs 的直接成纤维作用很少有报道。因此，本研究旨在探讨脂肪细胞 3T3-L1 对肝星状 LX-2 细胞的成纤维作用。结果表明，将 3T3-L1 脂肪细胞的上清液孵育 LX-2 细胞，会触发 LX-2 细胞中细胞外基质相关蛋白的表达，如α-平滑肌肌动蛋白（α-SMA）、I 型胶原（CO-I），并激活 TGFβ/Smad2/3 信号通路。此外，3T3-L1 细胞抑制胰岛素敏感性，激活内质网应激和自噬，促进纤维化的发展。这些结果支持了成熟脂肪细胞可以直接激活肝星状细胞的观点，并且建立脂肪细胞对 HSCs 的体外模型为筛选非酒精性脂肪性肝病等肝脏疾病的药物提供了新的思路。
