Apolipoprotein A-I (ApoA-I)

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Test Description

Apolipoprotein A-I (apoA-I) is the major protein component of high-density lipoprotein (HDL) in plasma. HDL particles can carry from one to four apoA-I molecules per particle. The liver and intestine synthesize lipid-poor apoA-I. The protein promotes cholesterol efflux from tissues (via the adenosine triphosphate-binding cassette transporter A1 [ABCA1] transporter) to the liver for excretion. ApoA-I is a cofactor for lecithin: cholesterol acyltransferase (LCAT) which is responsible for the formation of most plasma cholesteryl esters. ApoA-I is also a ligand for scavenger receptor type B1 (SR-B1). ApoA-I was also isolated as a prostacyclin (PGI2) stabilizing factor, and thus may have an anti-clotting effect.3 Defects in the gene that encodes apoA-I are associated with HDL deficiencies and systemic non-neuropathic amyloidosis.4

ApoA-I is a single polypeptide of 243 amino acid residues. Its sequence, as reported by Brewer et al.8 differs in several positions from earlier reports by Baker et al.9 ApoA-I contains no carbohydrate and has a molecular weight of approximately 28,000. This apolipoprotein has been reported to activate lecithin: cholesterol acyltransferase (LCAT), the enzyme that is responsible for cholesterol esterification in plasma. The other major HDL-associated protein, apoA-II, has a molecular weight of approximately 17,000 and consists of two identical 77-amino-acid peptide chains attached by a single disulfide bond. ApoA-II also contains no carbohydrate. Both apoA-I and apoA-II can self-associate in aqueous solutions, and this self-association results in major changes in secondary structure. ApoA-I is much more readily dissociated from HDL particles by ultracentrifugation than is apoA-II. Both apoA-I and apoA-II can combine with lecithin to form protein-phospholipid complexes with a hydrated density of HDL. ApoA-I also attaches to chylomicron surfaces and is released as the particle undergoes lipoprotein lipase-induced lipolysis.

The liver and intestine synthesize lipid-poor apoA-I, which can interact with the ABCA1 located on the arterial macrophages, transporting free cholesterol to the extracellular lipid poor HDL. Lipidation of the HDL particles generates HDL2.

Clinical Interpretation

Studies have compared the interaction of HDL and apoA-I with macrophages. While HDL binds to the cells, for example, via SR-BI, without being further internalized, apoA-I binding, cell association and internalization correlate with ABCA1 expression. The expression and regulation of these two receptors ensures that both lipid- free apoA-I and HDL can remove excess cholesterol from macrophages under different circumstances.9

The role of HDL and its major apolipoprotein apoA-I in cholesterol efflux from macrophages has been studied extensively, but the molecular details underlying this interaction are still incompletely understood. Lorenzi et al.7 compared the interactions of apoA-I and HDL with RAW264.7 macrophages, a cell system previously evolved as a well-accepted model for the study of cholesterol homeostasis in macrophages. Evaluation of the interactions between apoA-I and HDL with ABCA1 and SR-BI demonstrated that macrophages specifically bind HDL and apoA-I.7 While HDL competes for apoA-I binding, apoA-I is not a competitor for HDL binding. This observation suggests that HDL and apoA-I are binding to macrophages, at least in part, through distinct receptors. For and lipid-free apoA-I are poor ligands for SR-BI, explaining the lack of competition of HDL  could be available for the competition of the apoA-I binding site by HDL.7 ApoE, and possibly lipoprotein X, are also cholesterol acceptor proteins.

SR-BI is recognized as the receptor that mediates selective uptake of cholesterol esters from HDL by the liver and steroidogenic organs.16,17 Moreover, SR-BI is a multi-functional, multi-ligand receptor that facilitates the binding of a wide array of native and modified lipoproteins. These findings not only suggest that HDL and apoA-I are interacting with distinct receptors, namely, SR-BI and ABCA1, but also that the interaction might be of specific importance under different conditions of altered cholesterol homeostasis. Moreover, it has been shown that the relative proportions of lipid-free apolipoproteins and mature HDL in the plasma can affect the relative activities of ABCA1- and SR-BI-mediated cholesterol efflux.12,13

Overexpression of ABCA1 has been shown to increase apoA-I binding to the cell surface.13 The direct interaction of apoA-I with ABCA1 is further supported by the study of both ABCA1 and apoA-I mutants. All ABCA1 mutants, except ABCA1 (WS590S), which fail to promote cholesterol efflux, also fail to cross-link apoA-I.8,14

The apoA family constitute the major proteins found in HDL and triglyceride-rich lipoproteins. ApoA, as part of HDL, is involved in the removal of free cholesterol from extrahepatic tissues and also plays a role in the activation of LCAT. ApoA activates the enzymes driving cholesterol transfer from the tissues into HDL and is also involved in HDL recognition and receptors binding in the liver.2 There are multiple forms of apoA, the most common being apoA-I and apoA-II. ApoA-I is the major “A” apolipoprotein attached to HDL. ApoA-I is found in greater proportion than apoA-II (about 3 to 1).3 The apoA-I concentration can be measured directly and corresponds with HDL levels. Lower levels of apoA commonly correlate with the presence of CAD and peripheral vascular disease.

ApoA-I may be a better predictor of atherogenic risk than HDL-C.4 Certain genetic disorders cause apoA-I deficiencies and associated low levels of HDL. These patients also tend to have hyperlipidemia with elevated LDL, which contributes to accelerated rates of atherosclerosis.

Treatment Considerations

The apolipoproteins within HDL are significant determinants of its function. Although not proven, therapeutic strategies that selectively increase apoA-I levels (HDL-P) may be more atheroprotective than those that increase levels of both apoA-I and apoA-II.9

ApoA-I may be increased with:

  • Drugs (e.g., carbamazepine, estrogens, ethanol, lovastatin, niacin, oral contraceptives, phenobarbital, pravastatin, and simvastatin)5,6
  • Familial hyperalphalipoproteinemia
  • Physical exercise
  • Pregnancy
  • Weight reduction

ApoA-I may be decreased with:

  • Chronic renal failure
  • Coronary artery disease
  • Drugs (e.g., androgens, beta blockers, diuretics, and progestins)
  • Familial hypoalphalipoproteinemia
  • Smoking
  • Uncontrolled diabetes2


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