Work

Chylomicronemia from GPIHBP1 autoantibodies

Year: 2020

Type: review

Abstract: Glycosylphosphatidylinositol-anchored HDL binding protein 1 (GPIHBP1), a glycosylphosphatidylinositol (GPI)anchored protein of capillary endothelial cells, is a crucial partner for LPL in plasma triglyceride metabolism (1, 2).GPIHBP1 captures LPL from the subendothelial spaces (where it is secreted by parenchymal cells) and shuttles LPL across endothelial cells to its site of action in the capillary lumen (Fig. 1A) (3).In the absence of GPIHBP1-mediated transport, LPL never reaches the capillary lumen and instead remains trapped within the interstitial spaces, where it is bound to heparan sulfate proteoglycans (HSPGs) (3, 4) (Fig. 1B, C).The LPL that is transported by GPIHBP1 into capillaries is essential for the margination of triglyceride-rich lipoproteins (TRLs) along the surface of capillary endothelial cells, allowing triglyceride hydrolysis to proceed (5).In the absence of a functional GPIHBP1, TRLs do not stop and simply "flow on by" in the bloodstream.The binding of GPIHBP1 also preserves the structural integrity of LPL (6).In the absence of GPIHBP1, the catalytic domain of LPL is inherently unstable and undergoes spontaneous unfolding and loss of catalytic activity (6).The binding of GPIHBP1 blocks this unfolding, even in the setting of physiologic inhibitors of LPL (e.g., ANGPTL4) that function by catalyzing the unfolding of LPL (7).The capacity of GPIHBP1 to stabilize LPL structure and activity focuses active LPL where it needs to be for TRL processing-on the surface of capillary endothelial cells (6-9).GPIHBP1 is a member of the lymphocyte antigen 6/ urokinase-type plasminogen activator receptor (LU) family of proteins (10).Mature GPIHBP1 has two functional domains-an N-terminal disordered acidic domain (containing a sulfated tyrosine and multiple aspartates and glutamates) and a three-fingered LU domain containing 10 Abstract Some cases of chylomicronemia are caused by autoantibodies against glycosylphosphatidylinositol-anchored HDL binding protein 1 (GPIHBP1), an endothelial cell protein that shuttles LPL to the capillary lumen.GPIHBP1 autoantibodies prevent binding and transport of LPL by GPIHBP1, thereby disrupting the lipolytic processing of triglyceride-rich lipoproteins.Here, we review the "GPIHBP1 autoantibody syndrome" and summarize clinical and laboratory findings in 22 patients.All patients had GPIHBP1 autoantibodies and chylomicronemia, but we did not find a correlation between triglyceride levels and autoantibody levels.Many of the patients had a history of pancreatitis, and most had clinical and/or serological evidence of autoimmune disease.IgA autoantibodies were present in all patients, and IgG4 autoantibodies were present in 19 of 22 patients.Patients with GPIHBP1 autoantibodies had low plasma LPL levels, consistent with impaired delivery of LPL into capillaries.Plasma levels of GPIHBP1, measured with a monoclonal antibody-based ELISA, were very low in 17 patients, reflecting the inability of the ELISA to detect GPIHBP1 in the presence of autoantibodies (immunoassay interference).However, GPIHBP1 levels were very high in five patients, indicating little capacity of their autoantibodies to interfere with the ELISA.Recently, several GPIHBP1 autoantibody syndrome patients were treated successfully with rituximab, resulting in the disappearance of GPIHBP1 autoantibodies and normalization of both plasma triglyceride and LPL levels.The GPIHBP1 autoantibody syndrome should be considered in any patient with newly acquired and unexplained chylomicronemia.

Source: Journal of Lipid Research

DOI: 10.1194/jlr.r120001116