Genetics
Genetic CETP deficiency loads HDL with apoE, apoC-III, ANGPTL3 and complement proteins, offering a clue why high HDL-C doesn't protect these patients (J Clin Lipidol 2019)
Original title: Shotgun proteomic analysis reveals proteome alterations in HDL of patients with cholesteryl ester transfer protein deficiency
Patients with genetic CETP deficiency have markedly altered HDL size and lipid composition and elevated HDL-cholesterol, yet are not protected from atherosclerotic cardiovascular disease, a paradox this study probed by shotgun proteomic analysis of ultracentrifugally isolated HDL from eight CETP-deficient patients and eight normolipidaemic controls. The analysis identified 79 HDL-associated proteins spanning lipid metabolism, protease inhibition, complement regulation and acute-phase response, including five potential newly identified HDL proteins such as ANGPTL3. Spectral counts of apolipoprotein E were significantly higher in CETP-deficient patients (60.3 versus 43.7, P < .001), consistent with earlier findings, and complement regulatory proteins C3, C4a, C4b and C9 were also enriched. ApoC-III and ANGPTL3, both linked to increased atherosclerotic cardiovascular disease, were likewise enriched in CETP-deficient HDL (35.9 versus 27.1 and 2.3 versus 0.4, P < .01). The authors propose these proteomic changes in CETP-deficient HDL may partly explain why these patients remain vulnerable to atherosclerosis despite high HDL-C.
Original abstract
Background: We previously reported that the patients with cholesteryl ester transfer protein (CETP) deficiency (CETP-D) show marked changes in the size and lipid compositions of high-density lipoprotein (HDL) and that they are not protected from atherosclerotic cardiovascular diseases, despite increased serum HDL-cholesterol (HDL-C) levels. HDL particles carry a variety of proteins, some of which are known to have antiatherogenic functions.
Objective: This study aimed to investigate the protein composition of HDL particles in patients with CETP-D.
Methods: Eight patients with complete deficiency of CETP and 8 normolipidemic healthy subjects were enrolled. We performed shotgun proteomic analysis to investigate the proteome of ultracentrifugally isolated HDL.
Results: We identified 79 HDL-associated proteins involved in lipid metabolism, protease inhibition, complement regulation, and acute-phase response, including 5 potential newly identified HDL-associated proteins such as angiopoietin-like3 (ANGPTL3). Spectral counts of apolipoprotein (apo) E were increased in patients with CETP-D compared with controls (60.3 ± 6.9 vs 43.7 ± 2.5, P < .001), which is concordant with our previous report. Complement regulatory proteins such as C3, C4a, C4b, and C9 were also significantly enriched in HDL from patients with CETP-D. Furthermore, apoC-III and ANGPTL3, both of which are now known to associate with increased atherosclerotic cardiovascular diseases, were enriched in patients with CETP-D compared with normolipidemic subjects (35.9 ± 5.3 vs 27.1 ± 3.7, 2.3 ± 1.1 vs 0.4 ± 1.1, respectively; P < .01).
Conclusion: We have characterized HDL-associated proteins in patients with CETP-D. We identified a significant increase in the amount of apoE, apoC-III, ANGPTL3, and complement regulatory proteins. These proteomic changes might be partly responsible for the enhanced atherogenicity of patients with CETP-D.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.