Familial high-density lipoprotein deficiency states and premature coronary heart disease

Abstract

High-density lipoprotein cholesterol (HDL-C) values <40 mg/dL have been shown to be an independent risk factor for coronary heart disease (CHD). Rare genetic disorders associated with marked human HDL deficiency include apolipoprotein A-I (apoA-I) deficiency with undetectable plasma apoA-I, which can be due to defects within the APOA1 gene resulting in lack of apoA-I secretion. Such patients have marked HDL deficiency, normal levels of triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C), and they can have xanthomas and premature CHD. ApoA-I variants with amino acid substitutions, especially in the region of amino acid residues 50–93 and 170–178, have been associated with amyloidosis. Patients with homozygous Tangier disease have defective cellular cholesterol efflux due to mutations in the adenosine-5′-triphosphate (ATP)-binding cassette transporter A1, detectable plasma apoA-I levels, and only pre-β1 HDL in their plasma. They have decreased LDL-C levels and can develop neuropathy and premature CHD. Patients with lecithin:cholesterol acyltransferase deficiency have both pre-β1 and α4 HDL present in their plasma and develop corneal opacities, anemia, proteinuria, and kidney failure. HDL deficiency has been associated with hypertriglyceridemia, obesity, insulin resistance, and diabetes. Common familial disorders associated with premature CHD and low HDL are: (1) dyslipidemia, seen in 15% of families, (2) combined hyperlipidemia, seen in 14% of families, and (3) hypoalphalipoproteinemia, seen in 4% of families. A common feature of all these disorders associated with premature CHD is a marked deficiency of very large α1 HDL. Niacin is currently the most optimal treatment strategy to raise HDL-C and normalize the HDL particle profile in these patients. Hot Topics in Cardiometabolic Disorders Volume 2 • Issue 3 • Year 2011 © FBCommunication Modena (Italy) Cite this article as: Schaefer EJ, Santos RD, Tani M, Schaefer PM, Asztalos BF. Familial high-density lipoprotein deficiency states and premature coronary heart disease. Hot Topics Cardiomet Disord 2011;2(3):7-16. E-mail: ernst.schaefer@tufts.edu Hot Topics in Cardiometabolic Disorders 2011;3:7-16 Copyright © 2011 FBCommunication s.r.l. a socio unico Downloaded from www.hottopicsin.com As shown in Figure 2-upper panel pre-β1 HDL is a very small disk with two molecules of apoA-I forming a belt (in yellow) around approximately 16 molecules of phospholipid (in blue), with a diameter of about 5.6 nm and a molecular weight of about 70 kDa. This particle is converted to small α4 HDL, which is a small disk with 2 molecules of apoA-I, but has about 26 molecules of phospholipid, and about 12 molecules of free cholesterol (in green), with a diameter of about 7.4 nm, and a molecular weight of about 80 kDa. Figure 2-lower panel depicts a model of medium spherical α3 HDL with 2 molecules of apoA-I, 1 molecule of apoA-II, with phospholipid and free cholesterol on its surface, and cholesteryl ester (in green) and TG (in purple) in the HDL core with a diameter of about 8.0 nm. The large spherical α2 HDL contains 4 molecules of apoA-I; 2 molecules of apoA-II, phospholipid, and free cholesterol on its surface; and cholesteryl ester and TG in its core, with a diameter of about 9.2 nm (see Figure 2–lower panel). The α1 HDL is very large and spherical with 8 molecules of apoA-I, phospholipid, and free cholesterol on its surface, and cholesteryl ester and TG in the core of HDL with a diameter of about 11.0 nm (see Figure 2–lower panel) [19]. In collaboration with George Rothblat’s laboratory, the authors studied the roles of HDL particles in ABCA1-, ABCG1-, and scavenger receptor class B type 1 (SRB1) mediated lipid flux [20-23]. It has been documented that only the small precursor HDL (pre-β1) was able to remove lipids (phospholipid and free cholesterol) from cells via the ABCA1 pathway, and that the bidirectional cell-lipid flux via the SRB1 mechanism was mediated by the larger HDL