Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany.
Cells. 2021 Aug 24;10(9):2184. doi: 10.3390/cells10092184.
Comprehending the molecular mechanisms underlying hepatic fibrogenesis is essential to the development of treatment. The hallmark of hepatic fibrosis is the development and deposition of excess fibrous connective tissue forcing tissue remodeling. Hepatic stellate cells (HSC) play a major role in the pathogenesis of liver fibrosis. Their activation via the transforming growth factor-β1 (TGF-β1) as a key mediator is considered the crucial event in the pathophysiology of hepatic fibrogenesis. It has been shown that Perilipin 5 (PLIN5), known as a lipid droplet structural protein that is highly expressed in oxidative tissue, can inhibit such activation through various mechanisms associated with lipid metabolism. This study aimed to investigate the possible influence of PLIN5 on TGF-β1 signaling. Our findings confirm the importance of PLIN5 in maintaining HSC quiescence in vivo and in vitro. PLIN5 overexpression suppresses the TGF-β1-SMAD2/3 and SNAIL signaling pathways as well as the activation of the signal transducers and activators of transcription 3 (STAT3). These findings derived from experiments in hepatic cell lines LX-2 and Col-GFP, in which overexpression of PLIN5 was able to downregulate the signaling pathways SMAD2/3 and SNAIL activated previously by TGF-β1 treatment. Furthermore, TGF-β1-mediatedinduction of extracellular matrix proteins, such as collagen type I (COL1), Fibronectin, and α-smooth muscle actin (α-SMA), was suppressed by PLIN5. Moreover, STAT3, which is interrelated with TGF-β1 was already basally activated in the cell lines and inhibited by PLIN5 overexpression, leading to a further reduction in HSC activity shown by lowered α-SMA expression. This extension of the intervening mechanisms presents PLIN5 as a potent and pleiotropic target in HSC activation.
理解肝纤维化发生的分子机制对于治疗方法的发展至关重要。肝纤维化的标志是过度纤维结缔组织的形成和沉积，迫使组织重塑。肝星状细胞（HSC）在肝纤维化的发病机制中起主要作用。它们通过转化生长因子-β1（TGF-β1）的激活作为关键介质被认为是肝纤维化发生的病理生理学中的关键事件。已经表明，Perilipin 5（PLIN5），作为一种在氧化组织中高度表达的脂滴结构蛋白，可以通过与脂质代谢相关的各种机制抑制这种激活。本研究旨在研究 PLIN5 对 TGF-β1 信号的可能影响。我们的研究结果证实了 PLIN5 在维持体内和体外 HSC 静止中的重要性。PLIN5 的过表达抑制 TGF-β1-SMAD2/3 和 SNAIL 信号通路以及信号转导和转录激活因子 3（STAT3）的激活。这些发现来自于在 LX-2 和 Col-GFP 肝细胞系中进行的实验，其中 PLIN5 的过表达能够下调 TGF-β1 处理先前激活的 SMAD2/3 和 SNAIL 信号通路。此外，PLIN5 还抑制 TGF-β1 介导的细胞外基质蛋白，如胶原 I（COL1）、纤维连接蛋白和α-平滑肌肌动蛋白（α-SMA）的诱导。此外，与 TGF-β1 相关的 STAT3 在细胞系中已经被基础激活，并被 PLIN5 的过表达抑制，导致 HSC 活性的进一步降低，表现为 α-SMA 表达降低。这些干预机制的扩展表明 PLIN5 是 HSC 激活的一种有效且多效的靶点。
