Autoantibodies against GPIHBP1 as a Cause of Hypertriglyceridemia

Abstract

BACKGROUND A protein that is expressed on capillary endothelial cells, called GPIHBP1 (glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1), binds lipoprotein lipase and shuttles it to its site of action in the capillary lumen. A deficiency in GPIHBP1 prevents lipoprotein lipase from reaching the capillary lumen. Patients with GPIHBP1 deficiency have low plasma levels of lipoprotein lipase, impaired intravascular hydrolysis of triglycerides, and severe hypertriglyceridemia (chylomicronemia). During the characterization of a monoclonal antibody–based immunoassay for GPIHBP1, we encountered two plasma samples (both from patients with chylomicronemia) that contained an interfering substance that made it impossible to measure GPIHBP1. That finding raised the possibility that those samples might contain GPIHBP1 autoantibodies. METHODS Using a combination of immunoassays, Western blot analyses, and immunocytochemical studies, we tested the two plasma samples (as well as samples from other patients with chylomicronemia) for the presence of GPIHBP1 autoantibodies. We also tested the ability of GPIHBP1 autoantibodies to block the binding of lipoprotein lipase to GPIHBP1. RESULTS We identified GPIHBP1 autoantibodies in six patients with chylomicronemia and found that these autoantibodies blocked the binding of lipoprotein lipase to GPIHBP1. As in patients with GPIHBP1 deficiency, those with GPIHBP1 autoantibodies had low plasma levels of lipoprotein lipase. Three of the six patients had systemic lupus erythematosus. One of these patients who had GPIHBP1 autoantibodies delivered a baby with plasma containing maternal GPIHBP1 autoantibodies; the infant had severe but transient chylomicronemia. Two of the patients with chylomicronemia and GPIHBP1 autoantibodies had a response to treatment with immunosuppressive agents. CONCLUSIONS In six patients with chylomicronemia, GPIHBP1 autoantibodies blocked the ability of GPIHBP1 to bind and transport lipoprotein lipase, thereby interfering with lipoprotein lipase–mediated processing of triglyceride-rich lipoproteins and causing severe hypertriglyceridemia.

An enzyme-linked immunosorbent assay for measuring GPIHBP1 levels in human plasma or serum

“…As negative controls, we included samples from a subject who was homozygous for a deletion of the entire GPIHBP1 gene 3 and two subjects who had a GPIHBP1-C89X nonsense mutation. 1 As expected, the GPIHBP1 serum levels in the “negative control samples” ( i.e. , samples from patients with GPIHBP1 mutations) were very low.…”

“…1 We had no difficulty in detecting GPIHBP1 in the plasma of a hypertriglyceridemic patient who had a genetic deficiency in LPL , whereas GPIHBP1 levels were extremely low in hypertriglyceridemic patients who had loss-of-function mutations in GPIHBP1 (missense, nonsense, or deletion). 1 In patients with GPIHBP1 deficiency, the plasma LPL levels were also low, reflecting markedly reduced delivery of LPL to the capillary lumen. 1 …”

“…The sensitivity of our ELISA is similar to that of an earlier ELISA for GPIHBP1. 1, 2 Our GPIHBP1 ELISA allowed us to quantify GPIHBP1 in serum and plasma samples, even when the samples were lipemic. The range of GPIHBP1 levels in serum was broad in a small cohort of healthy subjects (576–1,626 pg/ml) and possibly broader in patients with cardiovascular and/or metabolic disease (392–4,654 pg/ml).…”

“…We also examined de-identified archived plasma samples from patients with loss-of-function mutations in GPIHBP1 . 1, 3, 13 Those samples had been sent to UCLA without identifiers; 1 accordingly, studies of those plasma samples were deemed exempt from institutional review board approval.…”

A Proposal of The New Mechanism on Remnant Lipoprotein Formation and Clearance after Food Intake

“…We have recently reported that the autoantibody against GPIHBP1 completely blocked LPL activity and induced severe hypertriglyceridemia without forming CM and VLDL remnants even after food intake [45]. Figure 4: LPL is secreted from adipocytes and move to interstitial space.…”