Chronic hypothyroidism induces abnormal structure of high-density lipoproteins and impaired kinetics of apolipoprotein A-I in the rat

Abnormal levels of plasma high-density lipoproteins (HDL) commonly reflect altered metabolism of the major HDL-apolipoprotein A-I (apo A-I). It is well known that thyroid hormones are involved in the regulation of lipoprotein metabolism, inducing significant changes in the concentration, size, and composition of plasma HDL. The purpose of this study was to evaluate the mechanisms responsible of the decreased HDL-apo A-I in chronic thyroidectomized rats (Htx) and to assess the role of HDL structure in apo A-I turnover. Htx rats were found to have a 3-fold increase in low-density lipoprotein-cholesterol (LDL-C), whereas HDL-C and apo A-I showed a 25.9% and 22.6% decrease compared to controls (P <.05), thus suggesting a defect in HDL metabolism. Turnover studies of apo A-I incorporated into normal HDL, using exogenous (125)I-radiolabeling, confirmed an altered fractional catabolic rate (FCR) in Htx rats (0.097 +/- 0.009 d(-1) v 0.154 +/- 0.026 d(-1) for Htx and control rats, respectively, P <.005). Apo A-I production rates calculated with autologous HDL data showed that apo A-I synthesis was decreased to a higher extent than the already reduced apo A-I catabolism, thus explaining the low apo A-I plasma levels in Htx rats. Composition analysis of HDL-Htx revealed increased phospholipid and apo E content, whereas apo A-IV was diminished. Such structural changes contribute to the reduced apo A-I catabolism as demonstrated with further kinetic turnover studies in normal rats treated with (125)I-radiolabeled apo A-I reincorporated into HDL isolated from plasma of Htx rats (FCR, 0.102 +/- 0.017 v 0.154 +/- 0.026 d(-1), for Htx and normal rats, respectively, P <.005). In summary, chronic hypothyroidism in rat a species that lacks cholesteryl ester transfer protein (CETP) activity is characterized by low HDL-C and apo A-I plasma levels as a result of a low apo A-I production rate that exceeds a decreased FCR. Both structural abnormalities of HDL and changes induced in the animal that affect HDL catabolism contribute to the low FCR of apo A-I in the hypothyroid state.