Winterfeldt Kayli, Tasin Fahim Rejanur, Sekhar Vandana, Siddiqi Shadab A
Division of Metabolic & Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 6900 Lake Nona Blvd., Room# 349, Orlando, FL 32827, USA.
Int J Mol Sci. 2025 May 15;26(10):4720. doi: 10.3390/ijms26104720.
Dyslipidemia is a well-known risk factor in the development and progression of atherosclerosis. VLDL plays a crucial role in maintaining lipid homeostasis; however, even minor fluctuations in its production, intracellular trafficking, and secretion can contribute to the progression of atherosclerosis. Fenofibrate is an FDA-approved drug that effectively lowers plasma triglycerides and VLDL-associated cholesterol while simultaneously increasing HDL levels. Although fenofibrate is a known PPARα agonist with several proposed mechanisms for its lipid-altering effects, its impact on the intracellular trafficking of VLDL has not yet been investigated. We observed that treatment of HepG2 cells with 50 µM of fenofibrate resulted in a significant reduction in VLDL secretion, as evidenced by a significant decrease in the secretion of H-labeled TAG, fluorescent TAG, and ApoB100 protein into the media. Using confocal microscopy to monitor VLDL intracellular trafficking, we observed a distinct change in VLDL triglyceride localization, suggesting delayed transport through the endoplasmic reticulum and Golgi. An immunoblot analysis revealed a decrease in Sar1B protein expression, a key regulator of COPII protein recruitment, which is essential for VTV formation and intracellular VLDL trafficking, the rate-limiting step in VLDL secretion. Our data reveal a novel mechanism by which fenofibrate alters the lipid profile by interfering with intracellular VLDL trafficking in hepatocytes.
血脂异常是动脉粥样硬化发生和发展过程中一个众所周知的危险因素。极低密度脂蛋白（VLDL）在维持脂质稳态中起关键作用；然而，即使其产生、细胞内运输和分泌出现微小波动，也可能导致动脉粥样硬化的进展。非诺贝特是一种经美国食品药品监督管理局（FDA）批准的药物，可有效降低血浆甘油三酯和与VLDL相关的胆固醇，同时提高高密度脂蛋白（HDL）水平。尽管非诺贝特是一种已知的过氧化物酶体增殖物激活受体α（PPARα）激动剂，其脂质改变作用有多种提出的机制，但其对VLDL细胞内运输的影响尚未得到研究。我们观察到，用50μM非诺贝特处理HepG2细胞会导致VLDL分泌显著减少，这可通过培养基中H标记的甘油三酯（TAG）、荧光TAG和载脂蛋白B100（ApoB100）蛋白分泌的显著减少来证明。使用共聚焦显微镜监测VLDL细胞内运输，我们观察到VLDL甘油三酯定位有明显变化，提示通过内质网和高尔基体的运输延迟。免疫印迹分析显示，Sar1B蛋白表达降低，Sar1B是II型COP蛋白募集的关键调节因子，对VLDL运输囊泡（VTV）形成和细胞内VLDL运输至关重要，而这是VLDL分泌的限速步骤。我们的数据揭示了一种新机制，即非诺贝特通过干扰肝细胞内VLDL运输来改变脂质谱。
