HDL clearance and receptor-mediated catabolism of LDL are reduced in hypothyroid rats

Abstract

Hypercholesterolemia associated with hypothyroidism is due partly to increased plasma LDL and partly to increased HDL cholesterol concentrations. The increase in LDL cholesterol has been shown to be secondary to reduced plasma clearance of LDL. To determine which catabolic route was thyroid dependent, the present study examined the effects of hypothyroidism on the receptor-mediated pathway and the ‘receptor-independent’ pathway of LDL metabolism. Wistar rats (327 ± 22 g; mean ± SD) were made hypothyroid by feeding propylthiouracil (0.1%, w/w) and rat 131I-LDL (rLDL; d = 1.019−1.050) and 125I-methylated-LDL (rLDL-CH 3) were simultaneously injected i.v. after which the rates of clearance of labelled LDL in plasma were determined over 0–54 h. Total LDL and ‘receptor-independent’ clearances were represented by clearance of 131I-rLDL and 125I-rLDL-CH 3 respectively and the difference between the two represented high affinity receptor-mediated clearance. The data were analyzed using Matthews' model and the fractional catabolic rates (FCR) were calculated. The FCR of rLDL clearance via the receptor-mediated pathway was 0.1042 ± 0.0112 pools/h (n = 6) in controls vs. 0.0613 ± 0.0079 pools/h (n = 6) in hypothyroid animals ( P < 0.01). The FCR via the ‘receptor-independent’ pathway was 0.0642 ± 0.0040 pools/h (n = 6) in controls vs. 0.0561 ± 0.0036 pools/h (n = 6) in hypothyroid animals (not significant). The plasma HDL cholesterol concentration was also increased in hypothyroid rats (70.4 ± 6.7 mg/dl) compared to control (53.3 ± 3.1 mg/dl) ( P < 0.025). The plasma clearance rate of rat high-density lipoprotein (rHDL, d = 1.125−1.210) was also observed to be reduced in hypothyroid group (0.0441 ± 0.0010 pools/h; n = 4) compared to controls (0.0564 ± 0.0034 pools/h; n = 4) ( P < 0.05) but the difference was less pronounced than that observed for rLDL. The activity distribution ratio (ADR), which measures the ratio of extravascular to intravascular lipoprotein pools, was calculated from the clearance data. ADR of native LDL in control rats was higher than hypothyroid rats and correlated with increased plasma LDL observed in the latter. In contrast, the ADR of methylated LDL was <1.0 for both groups of rats amd may be due to a lack of interaction of rLDL-CH 3 with the endothelial high-affinity LDL receptors. These data indicate that thyroid hormone plays an essential regulatory role in catabolism of both LDL and HDL. We further postulate that the extravascular distribution of LDL may be regulated by high-affinity receptor binding of LDL.