GPIHBP1 and Plasma Triglyceride Metabolism

GPIHBP1, a GPI-anchored protein in capillary endothelial cells, is crucial for the lipolytic processing of triglyceride-rich lipoproteins (TRLs). GPIHBP1 shuttles lipoprotein lipase (LPL) to its site of action in the capillary lumen and is essential for the margination of TRLs along capillaries – such that lipolytic processing can proceed. GPIHBP1 also reduces the unfolding of the LPL catalytic domain, thereby stabilizing LPL catalytic activity. Many different GPIHBP1 mutations have been identified in patients with severe hypertriglyceridemia (chylomicronemia), the majority of which interfere with folding of the protein and abolish its capacity to bind and transport LPL. The discovery of GPIHBP1 has substantially revised our understanding of intravascular triglyceride metabolism but has also raised many new questions for future research.

TrendsGPIHBP1 is required for proper localization of LPL in capillaries.GPIHBP1 shuttles LPL from the interstitial spaces to the capillary lumen, where the enzyme hydrolyzes triglycerides in TRLs.In GPIHBP1 knockout mice, LPL does not reach the capillary lumen, resulting in impaired processing of TRLs, markedly increased plasma triglyceride levels, reduced delivery of lipid nutrients to parenchymal cells, increased de novo lipogenesis in adipose tissue, and increased uptake of TRL lipids by the liver.GPIHBP1 missense mutations in humans cause severe hypertriglyceridemia (chylomicronemia). The majority of these mutations interfere with the proper formation of disulfide bonds, resulting in the production of GPIHBP1 dimers and multimers with no capacity to bind LPL.