Abstract
We are pleased to have received the comments of Dr. Dullaart (1) who illustrates the difficulties of sorting out the multifaceted functions of high-density lipoprotein (HDL) and how they relate to atherogenesis and other pathophysiologic processes, and the design and interpretation of functional tests for HDL (2). In this respect, lipid transfers among lipoprotein classes play a crucial role in HDL formation and remodeling, and are determinants of HDL lipid composition and of the content of >80 proteins present in HDL fraction. In this respect, subjects with cholesteryl ester transfer protein deficiency show important proteomic changes in the HDL fraction (3). The HDL fraction, which contains the majority of lecithin-cholesterol acyltransferase (LCAT) and apo A-I, the LCAT cofactor, is the main system responsible for cholesterol esterification, a process that is essential for cholesterol stabilization in the plasma and that creates driving gradients of reverse cholesterol transport. In this setting, the entry of cholesterol into HDL from the other lipoprotein classes to undergo esterification is of great importance for cholesterol homeostasis. These considerations were the chief motivations for the development of an in vitro assay in our laboratory, which determines the simultaneous transfer of the esterified and unesterified cholesterol forms, triglycerides and phospholipids to HDL to approach the dynamics of lipid transfers in the plasma. This is a practical and reproducible method, which can eventually undergo automatization for the clinical laboratory (4).
In previous studies, we showed in patients with coronary artery disease (CAD) that a lower entry of unesterified cholesterol and esterified cholesterol into the HDL fraction is an independent CAD predictor (5). In subsequent studies, harmful life-style habits and diseases (sedentary life style, bedridden subjects, familial hypercholesterolemia, heart transplantation, and metabolic syndrome) were associated with lower transfer of cholesterol to HDL patients. Because lipid transfers are bidirectional and in the current assay only the HDL entry but not the HDL exit of the four lipids is measured, decreased or increased transfer of a given lipid to HDL is not necessarily accompanied by changes in the lipid composition of HDL as occurred in our recent study.
The four lipid transfers are not only defined by the action of the transfer proteins and the enzymes acting on plasma lipid metabolism but also by the number particles and composition of the other lipoprotein classes that compete with HDL to receive lipids, and there are probably other still unknown mechanisms at play. As emphasized by Dr. Dullaart, these intervening factors are not individually characterized in the in vitro assay, which deals with the resultant fluxes from all these variables.
Dr. Dullaart suggests that in hypothyroidism, tests such as the cholesterol efflux from cells and a measurement of the HDL anti-inflammatory capacity (6) should be performed. In fact, Jung et al. (7) found that the cholesterol efflux was diminished in hypothyroidism but did not improve after hormone substitution. To our knowledge, HDL anti-inflammatory assays have not been reported in hypothyroid patients, and we agree that this would be an important piece of information in this field.
In conclusion, in our study, there was a trend for diminished transfer of lipids in hypothyroidism that was corrected by the increase in the recipient HDL fraction; HDL-cholesterol elevation in those patients occurred through apparently unrelated mechanisms. Those findings suggest alterations in the complex process of lipid exchanges among lipoproteins, but the importance of these alterations to overall cholesterol homeostasis under thyroid hormone deficiency is indeed difficult to characterize.