We identified a family with a functional mutation in SR-BI. The mutation carriers had increased HDL cholesterol levels and a reduction in cholesterol efflux from macrophages but no significant increase in atherosclerosis. Reduced SR-BI function was associated with altered platelet function and decreased adrenal steroidogenesis. (Funded by the European Community and others.).

Both HDL size and HDL particle concentration were independently associated with other cardiovascular risk factors and with the risk for CAD. The relationship between HDL size and CAD risk was explained by markers associated with the metabolic syndrome, indicating that part of the relationship between HDL cholesterol and CAD risk is merely a reflection of this metabolic risk.

Objective-GPIHBP1 is an endothelial cell protein that binds lipoprotein lipase (LPL) and chylomicrons. Because GPIHBP1 deficiency causes chylomicronemia in mice, we sought to determine whether some cases of chylomicronemia in humans could be attributable to defective GPIHBP1 proteins. Methods and Results-Patients with severe hypertriglyceridemia (nϭ60, with plasma triglycerides above the 95th percentile for age and gender) were screened for mutations in GPIHBP1. A homozygous GPIHBP1 mutation (c.344AϾC) that changed a highly conserved glutamine at residue 115 to a proline (p.Q115P) was identified in a 33-year-old male with lifelong chylomicronemia. The patient had failure-to-thrive as a child but had no history of pancreatitis. He had no mutations in LPL, APOA5, or APOC2. The Q115P substitution did not affect the ability of GPIHBP1 to reach the cell surface. However, unlike wild-type GPIHBP1, GPIHBP1-Q115P lacked the ability to bind LPL or chylomicrons (d Ͻ 1.006 g/mL lipoproteins from Gpihbp1 Ϫ/Ϫ mice). Mouse GPIHBP1 with the corresponding mutation (Q114P) also could not bind LPL. Conclusions-A homozygous missense mutation in GPIHBP1 (Q115P) was identified in a patient with chylomicronemia.The mutation eliminated the ability of GPIHBP1 to bind LPL and chylomicrons, strongly suggesting that it caused the patient's chylomicronemia. See accompanying article on page 792Mice lacking GPIHBP1 manifest severe chylomicronemia, even on a low-fat chow diet, with plasma triglycerides Ͼ2000 mg/dL. 2 GPIHBP1 is found on the luminal surface of capillaries in heart, skeletal muscle, and adipose tissue, 2 where the lipolytic processing of triglyceride-rich lipoproteins occurs. 3 Transfection of a GPIHBP1 expression vector into CHO cells confers the ability to bind LPL, chylomicrons, as well as apo-AV-phospholipid disks. 2 The ability of GPIHBP1-expressing cells to bind LPL and chylomicrons suggested that GPIHBP1 might function as a platform for lipolysis on endothelial cells. 2 Two structural features of GPIHBP1 are important in the binding of LPL and chylomicrons. The first is an aminoterminal acidic domain, approximately 25 amino acids in length. Mutant GPIHBP1 proteins lacking all or part of the acidic domain are unable to bind LPL and chylomicrons. 4 The second is a Lymphocyte antigen 6 (Ly6) domain. Ly6 motifs, which contain either 8 or 10 cysteines with a characteristic spacing pattern, are found in a number of GPI-anchored proteins, for example CD59 and the urokinase-type plasminogen activator receptor (UPAR). 5 When the Ly6 domain of GPIHBP1 is replaced with the Ly6 domain from CD59, the chimeric protein reaches the cell surface but cannot bind LPL, even though the acidic domain of GPIHBP1 is intact. 4 All mammalian GPIHBP1 proteins share the acidic domain and the Ly6 domain (with 10 conserved cysteines). 6 The highest level of amino acid conservation lies within a portion of the Ly6 domain (residues 101 to 121 in human GPIHBP1, which contains the 6th and 7th cysteines of the Ly6 motif). 6 The finding of chylomicronemia...

Background-Recent studies in mice have established that an endothelial cell protein, glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), is essential for the lipolytic processing of triglyceride-rich lipoproteins. Methods and Results-We report the discovery of a homozygous missense mutation in GPIHBP1 in a young boy with severe chylomicronemia. The mutation, p.C65Y, replaces a conserved cysteine in the GPIHBP1 lymphocyte antigen 6 domain with a tyrosine and is predicted to perturb protein structure by interfering with the formation of a disulfide bond. Studies with transfected Chinese hamster ovary cells showed that GPIHBP1-C65Y reaches the cell surface but has lost the ability to bind lipoprotein lipase (LPL). When the GPIHBP1-C65Y homozygote was given an intravenous bolus of heparin, only trace amounts of LPL entered the plasma. We also observed very low levels of LPL in the postheparin plasma of a subject with chylomicronemia who was homozygous for a different GPIHBP1 mutation (p.Q115P). When the GPIHBP1-Q115P homozygote was given a 6-hour infusion of heparin, a significant amount of LPL appeared in the plasma, resulting in a fall in the plasma triglyceride levels from 1780 to 120 mg/dL. Conclusions-We identified a novel GPIHBP1 missense mutation (p.C65Y) associated with defective LPL binding in a young boy with severe chylomicronemia. We also show that homozygosity for the C65Y or Q115P mutations is associated with low levels of LPL in the postheparin plasma, demonstrating that GPIHBP1 is important for plasma triglyceride metabolism in humans. (Circ Cardiovasc Genet. 2010;3:169-178.)