Abstract
Mice lacking glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1) are unable to traffic LPL to the vascular lumen. Thus, triglyceride (TG) clearance is severely blunted, and mice are extremely hypertriglyceridemic. Paradoxically, mice lacking both GPIHBP1 and the LPL regulator, angiopoietin-like 4 (ANGPTL4), are far less hypertriglyceridemic. We sought to determine the mechanism by which Angptl4-/-Gpihbp1-/- double-knockout mice clear plasma TGs. We confirmed that, on a normal chow diet, plasma TG levels were lower in Angptl4-/-Gpihbp1-/- mice than in Gpihbp1-/- mice; however, the difference disappeared with administration of a high-fat diet. Although LPL remained mislocalized in double-knockout mice, plasma TG clearance in brown adipose tissue (BAT) increased compared with Gpihbp1-/- mice. Whole lipoprotein uptake was observed in the BAT of both Gpihbp1-/- and Angptl4-/-Gpihbp1-/- mice, but BAT lipase activity was significantly higher in the double-knockout mice. We conclude that Angptl4-/-Gpihbp1-/- mice clear plasma TGs primarily through a slow and noncanonical pathway that includes the uptake of whole lipoprotein particles.
Highlights
Mice lacking glycosylphosphatidylinositolanchored HDL-binding protein 1 (GPIHBP1) are unable to traffic LPL to the vascular lumen
In the absence of GPIHBP1, LPL is trapped in the interstitial spaces and is unable to access TG-rich lipoproteins in the circulation [6, 8]
The expected genetic deficiencies were verified by measuring expression of Gpihbp1 and Angptl4 by quantitative PCR (qPCR) (Fig. 1A, B)
Summary
Mice lacking glycosylphosphatidylinositolanchored HDL-binding protein 1 (GPIHBP1) are unable to traffic LPL to the vascular lumen. Triglyceride (TG) clearance is severely blunted, and mice are extremely hypertriglyceridemic Mice lacking both GPIHBP1 and the LPL regulator, angiopoietin-like 4 (ANGPTL4), are far less hypertriglyceridemic. We conclude that Angptl4 / Gpihbp1 / mice clear plasma TGs primarily through a slow and noncanonical pathway that includes the uptake of whole lipoprotein particles.—Cushing, E. Novel GPIHBP1-independent pathway for clearance of plasma TGs in Angptl4 / Gpihbp1 / mice. Preclinical studies suggest that targeting ANGPTL4 can lower plasma TGs in primates [14], and humans with homozygous deficiency in ANGPTL4 appear to be protected from cardiovascular disease [13, 14]. The intriguing phenotype of these mice strongly suggests the existence of a GPIHBP1-independent mechanism capable of substantial TG clearance in the absence of vascular LPL.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
