In collaboration with Drs. Stephen Young and Loren Fong at UCLA, we showed that GPIHBP1 is crucial for the lipolytic processing of triglyceride-rich lipoproteins. GPIHBP1 is a cell-surface protein of microvascular endothelial cells that binds lipoprotein lipase (LPL) in the subendothelial spaces and transports it to its site of action in the capillary lumen.
A major focus of my laboratory has been to define structure–function relationships of GPIHBP1 and LPL. GPIHBP1 has two domains, an acidic domain and a cysteine-rich domain (LU domain). The LU domain binds with high affinity to the carboxyl-terminus domain of LPL. We showed that hypertriglyceridemia can result from GPIHBP1 missense mutations in the LU domain that abolish GPIHBP1’s ability to bind and transport LPL. In collaboration with Dr. Katsuyuki Nakajima (Japan), we discovered that some cases of acquired chylomicronemia are due to autoantibodies against GPIHBP1’s LU domain.
In collaboration with Dr. Michael Ploug (Denmark), we showed that GPIHBP1’s acidic domain prevents the unfolding of the amino-terminus domain of LPL, thereby stabilizing LPL.
Recently, we upended the long-lived assumption that LPL is only active as a dimer. We showed that freshly secreted LPL is monomeric, and that LPL monomers bind to GPIHBP1 and are active.