Novel GPIHBP1-independent pathway for clearance of plasma TGs in Angptl4−/−Gpihbp1−/− mice

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.