Atheroprotective Reverse Cholesterol Transport Pathway Is Defective in Familial Hypercholesterolemia

Abstract

Objective-Low high-density lipoprotein (HDL) cholesterol levels are frequently observed in familial hypercholesterolemia (FH) and might be associated with functional alterations of HDL particles that may influence their efficaciousness in the reverse cholesterol transport pathway. Methods and Results-We evaluated key steps of the reverse cholesterol transport, ie, cellular free cholesterol efflux, cholesteryl ester transfer protein-mediated cholesteryl ester (CE) transfer from HDL to apolipoprotein B-containing lipoproteins, and hepatic HDL-CE uptake, in patients displaying FH (nϭ12) and in healthy normolipidemic control subjects (nϭ12). Large HDL2 particles isolated from FH patients displayed a reduced capacity to mediate free cholesterol efflux via both scavenger receptor-BI-and ABCG1-dependent pathways. A significant inverse relationship between scavenger receptor-BI-dependent HDL2 efflux capacity and carotid intima-media thickness (rϭϪ0.473; Pϭ0.0186), as well as between ABCG1-dependent HDL2 efflux capacity and carotid intima-media thickness (rϭϪ0.485; Pϭ0.0212), was detected. We also observed an elevated cholesteryl ester transfer protein-mediated CE transfer from HDL2 and HDL3 particles to low-density lipoprotein and a reduced capacity of HDL particles to deliver CEs to the liver. Conclusion-We demonstrated that the centripetal movement of cholesterol from peripheral tissues, including the vessel wall, to feces is defective in FH, thereby emphasizing its atherogenicity. Key Words: ABC transporter Ⅲ lipoproteins Ⅲ macrophages Ⅲ metabolism Ⅲ receptors F amilial hypercholesterolemia (FH) is a common inherited dominant autosomal disorder caused by mutations in the gene encoding the low-density lipoprotein (LDL) receptor. 1 These mutations lead to a reduced number of functional LDL receptors, resulting in diminished cellular uptake of LDL particles, LDL accumulation, and increased plasma levels of total cholesterol, LDL cholesterol, and premature atherosclerosis. 2,3 Within the arterial wall, macrophages take up modified LDL through a variety of scavenger receptors, mainly scavenger receptor (SR)-A and CD36, accumulate cholesteryl esters (CEs), and are progressively converted into lipid-rich foam cells that represent the hallmark of the atherosclerotic plaque. 4 Excess cholesterol in macrophages is eliminated via the process of reverse cholesterol transport (RCT), a pathway by which cholesterol from peripheral tissues is transported to the liver for biliary excretion. 5 During the past few years, the atheroprotective role of RCT has been clearly demonstrated in humans. 6 The first step in this pathway is the efflux of cholesterol from cells to extracellular acceptors, such as high-density lipoprotein (HDL) and apolipoprotein AI (apoAI). Cellular cholesterol efflux to lipid-free or lipid-poor apoAI occurs through a transporter belonging to the ATP binding cassette (ABC) family, ABCA1, 7 whereas free cholesterol efflux to mature HDL particles involves both ABCG1 8 and SR-BI. 9 The low HDL cholesterol levels...

Cellular cholesterol efflux and cholesterol loading capacity of serum: effects of LDL-apheresis

“…ABCA1-mediated CEC of patient sera before LDL-apheresis did not differ signifi cantly from that of control serum. Our data are consistent with previous observations obtained in FH patients of an impaired capacity of isolated HDL particles to mediate cellular free cholesterol effl ux via both SR-BI and ABCG1 pathways and a normal capacity of serum to mediate cellular cholesterol effl ux via the ABCA1 pathway ( 23 ). In addition, we extended, for the fi rst time, the same observation to FCH patients.…”

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

“…40,41 Dysfunctional HDL in cardiovascular disease is not limited to CAD and acute coronary syndrome (ACS). Also in other cardiovascular diseases, such as heart failure, 42 ischaemic cardiomyopathy, 43 heart transplantion, 44,45 as well as in many conditions that are known to increase cardiovascular risk such as diabetes, CKD, acute and chronic inflammatory diseases, or familial hypercholesterolemia, [46][47][48] HDL has been found to lose its atheroprotective characteristics.…”

Association Between Cholesterol Efflux Capacity and Atherosclerotic Cardiovascular Disease in Patients With Familial Hypercholesterolemia

“…Other traditional risk factors, such as age, male sex, smoking, hypertension, diabetes mellitus, and low high-density lipoprotein-cholesterol (HDL-C) 7,8 have been reported to be important for ASCVD in heterozygous FH. We have reported that pretreatment levels of LDL-C and Achilles tendon thickness were useful risk markers for determining patients at high risk for ASCVD in heterozygous FH.…”

“…Nenseter et al 22 revealed that cholesterol efflux capacity in patients with homozygous FH was reduced when compared with healthy controls, and Bellanger et al 7 demonstrated that large HDL2 particles isolated from 12 patients with FH displayed reduced cholesterol efflux capacity when compared with 12 healthy normolipidemic subjects. However, it had not been investigated whether cholesterol efflux capacity is a risk marker of ASCVD in patients with FH.…”