Abstract
The profound effects of hypothyroidism on lipoprotein metabolism have been known for decades. Such effects include high-density lipoprotein (HDL) cholesterol elevations, as confirmed in the recent study by Sigal et al. (1). Given the well-established inverse association of HDL cholesterol concentrations with atherosclerotic cardiovascular disease, there is continued interest in discerning the mechanisms that contribute to changes in HDL that occur during hypothyroidism. Among other pathways, the cholesteryl ester transfer protein (CETP)-mediated transfer of cholesteryl esters from HDL to apolipoprotein B-containing (triglyceride-rich) lipoproteins provides a key regulatory step in HDL metabolism. High HDL cholesterol levels are observed in genetic CETP deficiency, whereas HDL cholesterol increases consequent to pharmacological CETP inhibition (2). As appreciated by Sigal et al., several previous studies have demonstrated that hypothyroidism may decrease plasma cholesteryl ester transfer (CETP) mass or activity, measured either as the transfer of radiolabeled cholesteryl esters from endogenous HDL toward apolipoprotein B-containing (triglyceride-rich) lipoproteins (referred to in the study by Sigal et al.) (1), or as the transfer/exchange of radiolabeled cholesteryl esters between exogenously added low density lipoproteins and HDL (3), the latter type of assay reflecting the plasma level of active CETP independent from the endogenous plasma lipoproteins (3). In general, these earlier findings are consistent with an effect of low thyroid hormone status to impair the CETP-mediated cholesteryl ester transfer process, thereby conceivably contributing to an increase in HDL cholesterol.
The assay system used in the study by Sigal et al. (1) is based on the transfer of radiolabeled cholesteryl esters, unesterified cholesterol, triglycerides, and phospholipids from an artificial nanoparticle lipid emulsion to endogenous plasma HDL (4). With this assay system as a readout, they observed no effect of hypothyroidism on the accumulation of cholesteryl esters and other lipids in HDL (1). Notably, after adjustment for HDL cholesterol, as a crude measure of HDL mass, the transfer of cholesteryl esters, unesterified cholesterol, triglycerides, and phospholipids from the lipid emulsion to HDL were all attenuated in hypothyroidism (1). However, this assay system does not allow the specific contributions of CETP, lecithin:cholesterol acyltransferase (LCAT), and phospholipid transfer protein to the accumulation in the HDL fraction of the various radiolabeled lipids tested to be appropriately appreciated. Obviously, the lack of effect of hypothyroidism on cholesteryl ester transport from the lipid emulsion to HDL, as now reported by Sigal et al., does not explain why HDL cholesterol is increased in hypothyroidism. Moreover, Sigal et al. did not observe changes in CETP and LCAT mass or changes in HDL size and lipid composition during hypothyroidism (1), the latter finding contrasting with our earlier observations (3).
Taken together, we question the utility of the nanoparticle lipid emulsion assay system, as employed in the report by Sigal et al. (1), to interrogate specific abnormalities in key regulatory pathways involving HDL metabolism in the hypothyroid state. We propose to discern further the effect of thyroid dysfunction on metrics of HDL function, including its ability to promote cellular cholesterol efflux and its anti-inflammatory capacity, in order to understand better the role of HDL in hypothyroidism-associated atherosclerosis development.