Changes in apolipoprotein A-I impair its antiatherogenic function

HDL Forum Editor Professor Kerr-Anne Rye discusses experimental data from a study by A Hoang and co-workers, published in Diabetologia. These data suggest that modification of apolipoprotein A-I (apoA-I), the main apolipoprotein in high-density lipoprotein (HDL), can impair its antiatherogenic function and contribute to increased cardiovascular risk.

Hoang A, Murphy AJ, Coughlan MT et al. Advanced glycation of apolipoprotein A-I impairs its antiatherogenic properties. Diabetologia 2007;50:1770-9.

It is widely accepted that the HDL circulating in human plasma inhibit atherosclerosis by a number of mechanisms. One of the most widely studied of these mechanisms is reverse cholesterol transport, the process whereby apoA-I, in either the lipid-free form or as a constituent of HDL, accepts cholesterol that is exported from various cells, including macrophages in the artery wall. The cholesterol that is acquired by HDL in this way is esterified by the enzyme lecithin:cholesterol acyltransferase (LCAT) and then transported to the liver where it is excreted.

Persistent hyperglycaemia and oxidative stress in diabetes promotes the formation of advanced glycation end-products (AGEs). Increasing evidence suggests that AGEs play an important role in the pathogenesis of both macrovascular and microvascular complications of diabetes.

Researchers from the Baker Heart Research Institute, Melbourne, Australia investigated whether AGE-modification of apoA-I impairs its atheroprotective functions, by carrying out in vitro experiments with a human monocyte-macrophage cell line (THP-1), isolated human monocytes and a liver cell line transfected with ABCA1 or ABCG1. Lipid-free apoA-I and isolated plasma HDL were obtained from healthy human volunteers and AGE modified by incubation with physiologically relevant levels of ribose, glucose or the reactive α-oxoaldehyde methylglyoxal.

Compared with unmodified apoA-I and HDL, lipid-free apoA-I that had undergone AGE modification and AGE-modified HDL significantly reduced (by 40-70%) ABCA1- and ABCG1-mediated cholesterol efflux from the various cells.

This study describes for the first time that HDL and apoA-I that have been non-enzymatically glycated under hyperglycaemic conditions reduces the export of excess cholesterol from cells in the initial step of the reverse cholesterol transport pathway. Another study by Nobecourt and co-workers, published in Diabetologia 20071, has shown that non-enzymatic glycation of the apoA-I in HDL also impairs LCAT-mediated cholesterol esterification in the second step of the reverse cholesterol transport pathway. When both of these reports are considered together it would seem that AGE-modification of lipid-free apoA-I, or of the apoA-I in HDL, has the capacity to significantly impair reverse cholesterol transport. This may explain, at least in part, why the incidence of atherosclerosis is increased in subjects with diabetes. These data provide a rationale for targeting AGE reduction in the management of diabetic dyslipidaemia.

The other key observation from this paper is that cholesterol export from AGE-modified apoA-I can be partly restored by inhibiting non-enzymatic glycation with aminoguanidine and alagebrium chloride. Although aminoguanidine has a number of deleterious side effects, and cannot be used in humans, these results raise the possibility that alagebrium chloride, which is currently in Phase II clinical trials, may have beneficial effects that extend beyond its ability to improve endothelial and renal function, as well as heart failure.

1. Nobecourt E, Davies MJ, Brown BE et al. The impact of glycation on apolipoprotein A-I structure and its ability to activate lecithin:cholesterol acyltransferase. Diabetologia 2007;50:643-53.