Figure 2.

Schematic illustration of negative feedback loops in the link between proteinuria, hypoalbuminemia and hypertriglyceridemia mediated by Angptl4 and free fatty acids (FFA). Plasma FFA are non-covalently bound to albumin. Because of the preferential loss of albumin with low FFA content in nephrotic syndrome, there is a relative increase in circulating albumin with higher FFA content. As glomerular disease progresses towards severe proteinuria, hypoalbuminemia develops, and the combination of high albumin FFA content and lower plasma albumin levels increases the FFA to albumin ratio. This promotes entry of FFA into skeletal muscle, heart and adipose tissue, which causes upregulation of Angptl4, at least partially mediated by PPARs. Angptl4 secreted from these organs participates in two feedback loops: In the systemic loop, it binds to glomerular endothelial αvβ5 integrin and reduces proteinuria, the principal driver of nephrotic syndrome. In a local loop, it inactivates LPL in the same organs from which it is secreted to reduce the uptake of FFA (see above), thereby curtailing the stimulus for its own upregulation. The participation of exogenously administered recombinant wild type and mutant Angptl4 in the feedback loops is also illustrated. (reproduced from reference 20)