Integrated model of CM binding and hydrolysis on peripheral capillary endothelium.
Adipose tissue and striated muscle each synthesize LpL, regulated by the fasted/fed and active/sedentary metabolic states. HSPGs on the surfaces of these cells capture and internalize LpL for degradation. LpL that escapes degradation will be picked up by HSPGs and VLDL receptors on the basal surface of overlying endothelial cells for transcytosis to the luminal surface of capillaries (orange arrows). Heparan sulfate side-chains of syndecan and glypican are denoted by chains of small spheres. The major HSPGs of endothelium, syndecans and glypicans, move into detergent-insoluble membrane microdomains (rafts) rich in caveolin-1 (CAV1) upon clustering. On the apical surface, they encounter GPIHBP1, which should also move into rafts upon clustering. The highly negatively charged N-terminal domain of GPIHBP1 binds LpL with approximately 10-fold greater affinity than do endothelial HSPGs. Thus, after transcytosis, LpL should be torn away from syndecans and glypicans onto GPIHBP1 (pink arrows). Dimers of GPIHBP1 bind LpL and CMs, thereby providing a platform for CM docking and triglyceride lipolysis. These processes are facilitated by apoC-II and apoA-V. Lipolysis generates NEFAs that are transported by another raft molecule, CD36, across the endothelium and into adipocytes for energy storage (blue arrows) or into striated myocytes for combustion (green arrows). After hydrolysis of CM triglycerides, the endothelium releases apoB48 remnant lipoproteins that are rich in LpL, apoE, and cholesteryl ester back into the circulation (red arrow). Under normal circumstances, these remnant particles undergo safe, swift uptake by the liver.