Novel GPIHBP1-independent pathway for clearance of plasma TGs in 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 double-knockout mice clear plasma TGs. We confirmed that, on a normal chow diet, plasma TG levels were lower in mice than in 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 mice. Whole lipoprotein uptake was observed in the BAT of both and mice, but BAT lipase activity was significantly higher in the double-knockout mice. We conclude that mice clear plasma TGs primarily through a slow and noncanonical pathway that includes the uptake of whole lipoprotein particles.