ANGPTL3 deficiency impairs lipoprotein production and produces adaptive changes in hepatic lipid metabolism

• DOI: 10.1016/j.jlr.2024.100500
• Publication Date: 2024-01-21T04:31:57Z
• Authors: Kendall H. Burks; Yan Xie; Michael Gildea; In-Hyuk Jung; Sandip Mukherjee; Paul Lee; Upasana Pudupakkam; Ryan Wagoner; Ved Patel; Katherine Santana; Arturo Alisio; Ira J. Goldberg; Brian N. Finck; Edward A. Fisher; Nicholas O. Davidson; Nathan O. Stitziel
• Keywords: Catabolism; PCSK9

Angiopoietin-like protein 3 (ANGPTL3) is a hepatically secreted and therapeutic target for reducing plasma triglyceride-rich lipoproteins (TRL) low-density lipoprotein cholesterol (LDL). Although ANGPTL3 modulates the metabolism of circulating lipoproteins, its role in TRL assembly secretion remains unknown. CRISPR-associated 9 (CRISPR/Cas9) was used to HepG2 cells (ANGPTL3-/-) whereupon we observed ∼50% reduction ApoB100 secretion, accompanied by an increase early presecretory degradation predominantly lysosomal mechanism. Despite defective particle ANGPTL3-/- cells, targeted lipidomic analysis did not reveal neutral lipid accumulation but rather demonstrated decreased newly synthesized triglycerides increased fatty acid oxidation. Furthermore, RNA sequencing significantly altered expression key genes, including targets PPARα, consistent with anabolism catabolism. In contrast, CRISPR/Cas9 LDLR deletion result defect at baseline, proteasomal inhibition strongly induced compensatory late impaired secretion. Additionally, these ANGPTL3-/-;LDLR-/- rescued deficient LDL clearance LDLR-/- cells. Our findings suggest unanticipated intrahepatic ANGPTL3, whose function varies status. deficiency alone leads production fewer particles due defects that are associated adaptive changes metabolism. When absent, regulation degradation.