ABCA1-Derived Nascent High-Density Lipoprotein–Apolipoprotein AI and Lipids Metabolically Segregate

Abstract

Objective Reverse cholesterol transport (RCT) comprises cholesterol efflux from ABCA1-expressing macrophages to apo AI giving nascent high density lipoprotein (nHDL), esterification of nHDL-free cholesterol (FC), selective hepatic extraction of HDL-lipids, and hepatic conversion of HDL-cholesterol to bile salts, which are excreted. We tested this model by identifying the fates of nHDL-[3H]FC, [14C]PL, and [125I]apo AI in serum in vitro and in vivo. Approach and Results During in vitro incubation of human serum, nHDL-[3H]FC and [14C]PL rapidly transfer to HDL and low density lipoproteins (LDL; t1/2 = 2–7 min) while nHDL-[125I]apo AI transfers solely to HDL (t1/2<10 min) and to the lipid-free form (t1/2 >480 min). Following injection into mice nHDL-[3H]FC and [14C]PL rapidly transfer to liver (t1/2 ~ 2–3 min) whereas apo AI clears with t1/2 = ~460 min. The plasma nHDL-[3H]FC esterification rate is slow (0.46%/h) compared to hepatic uptake. Phospholipid transfer protein enhances nHDL-[14C]PL but not nHDL-[3H]FC transfer to cultured Huh7 hepatocytes. Conclusions nHDL-FC, PL, and apo AI enter different pathways in vivo. Most nHDL-[3H]FC and [14C]PL are rapidly extracted by the liver via scavenger receptor class B member 1 and spontaneous transfer; hepatic PL uptake is promoted by phospholipid transfer protein. nHDL-[125I]apo AI transfers to HDL and to the lipid-free form that can be recycled to nHDL formation. Cholesterol esterification by LCAT is a minor process in nHDL metabolism. These findings could guide the design of therapies that better mobilize peripheral tissue-FC to hepatic disposal.

ABCA1 variants rs2230806 (R219K), rs4149313 (M8831I), and rs9282541 (R230C) are associated with susceptibility to coronary heart disease

“…Of these genes, The ATP‐binding cassette transporter A1 (ABCA1) is an important one because it has the function of regulating the metabolism of cholesterol . ABCA1 is a membrane transporter protein that plays an essential role in the secretion of cellular‐free cholesterol and phospholipids, from cell membrane to lipid‐poor apolipoprotein AI, creating nascent high‐density lipoprotein (HDL) . Some genetic and related studies have shown that common polymorphisms in the ABCA1 gene can influence the function of ABCA1 transporter resulting in the altered biosynthesis of HDL‐C particles .…”

“…8,9 Some genetic and related studies have shown that common polymorphisms in the ABCA1 gene can influence the function of ABCA1 transporter resulting in the altered biosynthesis of HDL-C particles. 9 Among the normal people and the CHD population, the most common way of ABCA1 gene mutation is single nucleotide polymorphism (SNP), and the DNA sequence polymorphism caused by single nucleotide variation is the most common type of human genetic variation, accounting for more than 90% of the known polymorphism. 10 In recent years, a number of studies have shown that the distribution frequency of specific ABCA1 gene SNPs in different regions and populations is significantly different, and the effects on plasma HDL-C level and the incidence and severity of CHD are also different.…”

Directional ABCA1-mediated cholesterol efflux and apoB-lipoprotein secretion in the retinal pigment epithelium

“…When radiolabeled cholesterol was used in the 18 h HDL formation assay, the results were the same as with radiolabeled apoA-I: two HDL particle species, 12 and 7 nm in hydrodynamic diameter, could be detected (data not shown). We (42,50) and others (53) have previously shown that macrophages, hepatocytes, and other cell types that express either endogenous or exogenous ABCA1 form nascent HDL in two species that differ in size: the hydrodynamic diameter of the larger species at the peak center varies from 10 to >13 nm, depending on cell type, cholesterol loading, cell density, and other factors, while the hydrodynamic diameter of the smaller species at the peak center is confined to a more narrow range of 7-8 nm; the larger-sized species normally dominates over the smaller-sized species in the amount of apoA-I, cholesterol, and choline-phospholipid. Nascent HDL formation by ARPE-19 cells closely follows this general paradigm.…”

ABCA1 Variants rs1800977 (C69T) and rs9282541 (R230C) Are Associated with Susceptibility to Type 2 Diabetes

“…Among these genes, ABCA1 is an important one, because it has the function of modifying β-cells and, more importantly, it can regulate the metabolism of cholesterol [6,7]. ATP-binding cassette A1 transporter (ABCA1) is a membrane transporter protein that plays an essential role in the secretion of cellular free cholesterol and phospholipids from the cell membrane to lipid-poor apolipoprotein A-I, creating nascent high-density lipoprotein (HDL) [8,9]. Some genetic and related studies have shown that common polymorphisms in the ABCA1 gene can influence the function of ABCA1 transporter, resulting in an altered biosynthesis of HDL-C particles, as well as insulin secretion [9].…”

“…ATP-binding cassette A1 transporter (ABCA1) is a membrane transporter protein that plays an essential role in the secretion of cellular free cholesterol and phospholipids from the cell membrane to lipid-poor apolipoprotein A-I, creating nascent high-density lipoprotein (HDL) [8,9]. Some genetic and related studies have shown that common polymorphisms in the ABCA1 gene can influence the function of ABCA1 transporter, resulting in an altered biosynthesis of HDL-C particles, as well as insulin secretion [9]. Furthermore, impaired insulin secretion has been reported in persons with ABCA1 loss-of-function mutations, and reduced function of the ABCA1 transporter may be involved in the pathogenesis of T2DM [10,11].…”