Abstract 1202: Hyperthyroidism Decreases Plasma HDL Cholesterol by Inhibition of Hepatic ABCA1 Expression
Background- Thyroid dysfunction affects whole body cholesterol homeostasis by influencing plasma levels of low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). Plasma HDL-C levels are regulated by hepatic uptake via Scavenger receptor-BI (SR-BI) and by hepatic expression of ABCA1, which facilitates the efflux of cholesterol to nascent or preβ HDL. The aim of the study was to investigate whether reduced plasma HDL-C levels in hyperthyroidism are due to changes in hepatic expression of SR-BI or ABCA1.
Methods and Results- After two weeks of treatment with 360 nmoles/kg·d of triiodothyronine (T3), plasma total cholesterol and apoA-I levels of T3-treated mice were decreased by 40% and by 30%, when compared to control mice (P<0.001 and P<0.01, respectively). FPLC fractionation analysis of pooled plasma samples revealed a 40% decrease of HDL-C levels in hyperthyroid mice with no alterations of apoB-containing lipoproteins. Moreover, biliary and hepatic cholesterol concentration were increased 2.6-fold and 1.4-fold in T3-treated mice, when compared to controls (P<0.001 and P<0.001, respectively). To test whether the decrease in plasma HDL-C was caused by increased catabolism, [3H] HDL-C turnover studies were performed. Interestingly, both control and hyperthyroid mice showed identical plasma clearance of [3H] HDL-C. Analysis of hepatic ABCA1 and SR-BI expression showed a marked downregulation of ABCA1 protein in hyperthyroid mice (−32%, P=0.03), with no changes of SR-BI expression.
Conclusions- Hyperthyroidism in mice resulted in a dramatic decrease of systemic HDL-C levels which was associated with a marked downregulation of hepatic ABCA1, indicating that reduced plasma HDL-C levels in hyperthyroidism are due to diminished production and not to increased clearance. We feel that our results add essential information for the proposed employment of liver-specific thyromimetics as therapeutic agents for the treatment of dyslipemia.