Capacity of HDL to Efflux Cellular Cholesterol from Lipid-Loaded Macrophages Is Reduced in Patients with Familial Hypercholesterolemia

Shiva Ganjali; Susan Hosseini; Manfredi Rizzo; Anatol Kontush; Amirhossein Sahebkar

doi:10.3390/metabo13020197

Capacity of HDL to Efflux Cellular Cholesterol from Lipid-Loaded Macrophages Is Reduced in Patients with Familial Hypercholesterolemia

Metabolites. 2023 Jan 29;13(2):197. doi: 10.3390/metabo13020197.

Authors

Shiva Ganjali¹, Susan Hosseini², Manfredi Rizzo³, Anatol Kontush⁴, Amirhossein Sahebkar^{5

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Affiliations

¹ Department of Medical Biotechnology and Nanotechnology, Mashhad University of Medical Sciences, Mashhad, Iran.
² Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
³ Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, School of Medicine, University of Palermo, 90133 Palermo, Italy.
⁴ Cardiovascular Diseases Research Unit, National Institute of Health and Medical Research (INSERM), Metabolism and Nutrition, ICAN, Sorbonne University, F-75013 Paris, France.
⁵ Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
⁶ Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
⁷ Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.

Abstract

This study aimed to evaluate the high-density lipoprotein (HDL) capacity to efflux cellular cholesterol from lipid-loaded macrophages to find a reliable and low-cost biomarker with the purpose of better evaluating the risk of premature cardiovascular (CV) events in FH patients. This case-controlled study comprised 16 homozygous (HOFH) and 18 heterozygous (HEFH) FH patients, as well as 20 healthy subjects recruited as controls. Two main subfractions of HDL (HDL2 (d = 1.063-1.125 g/mL) and HDL3 (d = 1.125-1.210 g/mL)) were isolated from the patients' serum samples using sequential ultracentrifugation. After compositional characterization, the capacity of HDL to efflux cholesterol (CEC%) from lipid-laden macrophages was measured. The HDL2 and HDL3 subfractions showed some differences in lipid and protein composition between the studied groups. In addition, both HDL subfractions (p < 0.001) revealed significantly reduced CEC% in HOFH patients (HDL2: 2.5 ± 0.1 and HDL3: 3.2 ± 0.2) in comparison with the HEFH (HDL2: 3.2 ± 0.1% and HDL3: 4.1 ± 0.2%) and healthy (HDL2: 3.3 ± 0.2% and HDL3: 4.5 ± 0.3%) subjects. Additionally, multinomial logistic regression results indicated that the CEC% of both HDL2 (OR: 0.091; 95% CI: 0.018-0.452, p < 0.01) and HDL3 (OR: 0.118; 95% CI: 0.035-0.399, p < 0.01) subfractions are strongly and inversely associated with the homozygous form of FH. A decreased capacity of HDL particles to efflux cholesterol from macrophages might identify homozygous FH patients who are at elevated risk for premature CVDs. Prospective studies with a large sample size are warranted to evaluate this hypothesis.

Keywords: HDL cholesterol efflux; familial hypercholesterolemia; macrophage.

Grants and funding

We gratefully acknowledge support by grants from the Mashhad University of Medical Sciences (Grant no: 961927), as well as continuous support by INSERM (Paris, France) and Sorbonne University (Paris, France).