Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
Cell-Based Analysis Unit, Reference Laboratory, Egyptian Drug Authority, Cairo 12618, Egypt.
Int J Mol Sci. 2023 Jan 5;24(2):1034. doi: 10.3390/ijms24021034.
Pathogenesis roles of phospholipids (PLs) in nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. This study investigated the role of PLs in the progression of NAFLD among obese individuals via studying the alterations in serum PL composition throughout the spectrum of disease progression and evaluating the effects of specific phosphatidylethanolamines (PEs) on FLD development in vitro. A total of 203 obese subjects, who were undergoing bariatric surgery, were included in this study. They were histologically classified into 80 controls (C) with normal liver histology, 93 patients with simple hepatic steatosis (SS), 16 with borderline nonalcoholic steatohepatitis (B-NASH) and 14 with progressive NASH (NASH). Serum PLs were profiled by automated electrospray ionization tandem mass spectrometry (ESI-MS/MS). HepG2 (hepatoma cells) and LX2 (immortalized hepatic stellate cells or HSCs) were used to explore the roles of PL in NAFLD/NASH development. Several PLs and their relative ratios were significantly associated with NAFLD progression, especially those involving PE. Incubation of HepG2 cells with two phosphatidylethanolamines (PEs), PE (34:1) and PE (36:2), resulted in significant inhibition of cell proliferation, reduction of mitochondrial mass and membrane potential, induction of lipid accumulation and mitochondrial ROS production. Meanwhile, treatment of LX2 cells with both PEs markedly increased cell activation and migration. These effects were associated with a significant change in the expression levels of genes involved in lipogenesis, lipid oxidation, autophagy, apoptosis, inflammation, and fibrosis. Thus, our study demonstrated that elevated level of PEs increases susceptibility to the disease progression of obesity associated NAFLD, likely through a causal cascade of impacts on the function of different liver cells.
磷脂 (PLs) 在非酒精性脂肪性肝病 (NAFLD) 中的发病机制作用仍不完全清楚。本研究通过研究疾病进展过程中血清 PL 组成的变化，以及评估特定磷脂酰乙醇胺 (PEs) 对体外 FLD 发展的影响，来研究 PL 在肥胖个体中 NAFLD 进展中的作用。共有 203 名接受减肥手术的肥胖患者纳入本研究。他们的肝组织学分类为 80 名正常肝组织学的对照组 (C)、93 名单纯性肝脂肪变性 (SS) 患者、16 名边界性非酒精性脂肪性肝炎 (B-NASH) 患者和 14 名进展性 NASH (NASH) 患者。采用自动化电喷雾电离串联质谱 (ESI-MS/MS) 对血清 PL 进行分析。HepG2(肝癌细胞)和 LX2(永生化的肝星状细胞或 HSCs)用于研究 PL 在 NAFLD/NASH 发展中的作用。几种 PL 及其相对比值与 NAFLD 进展显著相关，特别是涉及 PE 的比值。用两种磷脂酰乙醇胺 (PEs)，PE (34:1) 和 PE (36:2) 孵育 HepG2 细胞，导致细胞增殖显著抑制、线粒体质量和膜电位降低、脂质积累和线粒体 ROS 产生诱导。同时，PEs 处理 LX2 细胞可显著增加细胞激活和迁移。这些作用与参与脂肪生成、脂质氧化、自噬、凋亡、炎症和纤维化的基因表达水平的显著变化相关。因此，我们的研究表明，PE 水平的升高增加了肥胖相关 NAFLD 疾病进展的易感性，可能通过对不同肝细胞功能的因果级联影响来实现。
