Abstract 115: Angptl3 Deficiency Impairs Triglyceride-rich Lipoprotein Production and Produces Adaptive Changes in Hepatic Lipid Metabolism

• DOI: 10.1161/atvb.43.suppl_1.115
• Publication Date: 2023-10-02T14:09:33Z
• Authors: Kendall H Burks; Yan Xie; Michael Gildea; Thomas Neufeld; Arturo Alisio; Edward Fisher; Nicholas Davidson; Nathan O Stitziel
• Keywords: Lipid droplet; PCSK9

Rationale: Angiopoietin-like protein 3 (ANGPTL3) is a hepatically secreted and therapeutic target for reducing plasma triglyceride-rich lipoproteins low-density lipoprotein cholesterol (LDL). Although ANGPTL3 modulates lipolytic pathways in the metabolism of circulating lipoproteins, its potential hepatocyte-specific role very (VLDL) assembly secretion remains unknown. Methods: We established hepatocyte cell culture systems, including CRISPR/Cas9-edited “knock out” (KO) HepG2 cells isogenic wild type controls. Radiolabeling was used to quantify apolipoprotein triglyceride synthesis secretion. LDL receptor (LDLR) expression function were determined using western blot, flow cytometry, confocal microscopy. Bulk RNA sequencing compare global transcript-level changes between KO cells. Intracellular neutral lipid species quantified by mass spectrometry-based targeted lipidomics. Results: observed statistically significant reduction approximately 50% B100 (apoB100) relative type. also reductions ranging from 30-50% radiolabeled triglycerides Furthermore, showed increased LDLR uptake BODIPY-labeled compared demonstrated significantly altered key genes within GO terms related metabolic processes associated subcellular compartments. Targeted lipidomic analysis exhibited seven 47 analyzed; overall, accumulation not Conclusions: Our results point an important intrahepatic ANGPTL3, suggesting deficiency leads production fewer particles corresponding adaptive hepatic metabolism.