Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan.
Liver Transplantation Center, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan.
Nutrients. 2020 Jan 20;12(1):270. doi: 10.3390/nu12010270.
Non-alcoholic fatty liver disease (NAFLD), the leading cause of chronic liver diseases worldwide, ranges from simple steatosis to steatohepatitis, with the risk for progressive fibrosis or even cirrhosis. While simple steatosis is a relatively benign condition, the buildup of toxic lipid metabolites can induce chronic inflammation, ultimately triggering disease progression. Pigment epithelium-derived factor (PEDF) is a secreted, multifunctional glycoprotein with lipid metabolic activities. PEDF promotes lipolysis through binding to adipose triglyceride lipase (ATGL), a key enzyme for triglyceride breakdown. In the current study, we aimed to delineate how changes in PEDF expression affect hepatic lipid accumulation. Our data revealed that hepatic PEDF was downregulated in a mouse NAFLD model. We further showed that decreased PEDF levels in hepatocytes in vitro resulted in elevated fatty acid uptake and lipid droplet formation, with concomitant upregulation of fatty acid transport proteins CD36 and fatty acid binding protein 1 (FABP1). RNA sequencing analysis of PEDF knocked down hepatocytes revealed an alteration in gene expression profile toward lipid accumulation. Additionally, decreased PEDF promotes mobilization of fatty acids, an observation distinct from blocking ATGL activity. Taken together, our data suggest that hepatic PEDF downregulation causes molecular changes that favor triglyceride accumulation, which may further lead to NAFLD progression.
非酒精性脂肪性肝病（NAFLD）是全球慢性肝病的主要病因，其范围从单纯性脂肪变性到脂肪性肝炎，存在进行性纤维化甚至肝硬化的风险。虽然单纯性脂肪变性是一种相对良性的情况，但有毒脂质代谢物的积累会引起慢性炎症，最终导致疾病进展。色素上皮衍生因子（PEDF）是一种具有脂质代谢活性的分泌型多功能糖蛋白。PEDF 通过与脂肪甘油三酯脂肪酶（ATGL）结合来促进脂肪分解，ATGL 是甘油三酯分解的关键酶。在本研究中，我们旨在阐明 PEDF 表达的变化如何影响肝脏脂质积累。我们的数据显示，在小鼠 NAFLD 模型中，肝 PEDF 表达下调。我们进一步表明，体外肝细胞中 PEDF 水平降低导致脂肪酸摄取和脂滴形成增加，同时脂肪酸转运蛋白 CD36 和脂肪酸结合蛋白 1（FABP1）上调。对 PEDF 敲低的肝细胞进行 RNA 测序分析显示，脂质积累的基因表达谱发生了改变。此外，PEDF 减少促进脂肪酸的动员，这与阻断 ATGL 活性的观察结果不同。总之，我们的数据表明，肝 PEDF 下调导致有利于甘油三酯积累的分子变化，这可能进一步导致 NAFLD 进展。
