Triiodothyronine increases rat apolipoprotein A‐I synthesis and alters high‐density lipoprotein composition in vivo

Abstract

The effects of altered serum 3,3',5-triiodothyronine levels on rat lipoprotein metabolism were examined. Daily injections of the hormone (50 pg/lOO g body mass) over a period of six days led to an increase of 6.4-fold in the hepatic mRNA level for apolipoprotein(apo)A-I, and a 21% increase in serum apoA-I levels. 12 h after a single injection of 3,3',5-triiodothyronine the rate of [14C]leucine incorporation into apoA-I increased 2.1 fold. Conversely, in hypothyroid rats there was a decrease in hepatic mRNA levels for apoA-I and a decreased rate of [14C]leucine incorporation into apoA-I. The increase in hepatic apoA-I mRNA levels following 3,3',5-triiodothyronine treatment occurred prior to significant changes in serum triacylglycerol levels. High-density lipoprotein (HDL) particles isolated from the serum of hyperthyroid rats were smaller and enriched in apoA-I compared to apoA-IV and apoE. Similar changes in HDL composition were observed following in vitro incubations of normal rat serum with purified rat apoA-I. The results suggest that during altered thyroid status, changes in serum HDL size and composition occur in association with significant changes in apoA-I gene expression.Interest in serum high-density lipoprotein (HDL) levels arises from their postulated role in reverse cholesterol transport [l] and on the basis of their negative correlation with the incidence of coronary heart disease [2, 31. Within this class of lipoproteins there is, however, considerable diversity in both size and composition [4, 51. Some of the heterogeneity of HDL results from changes in lipid composition mediated by lipidmodifying enzymes and exchange proteins. Other sources of the heterogeneity are the result of different apolipoprotein composition. This heterogeneity has functional significance. Studies on the transfer of cholesterol from cell membranes to serum lipoproteins for example [6], demonstrate a role for small apolipoprotein(apo)A-I-containing HDL particles as the initial cholesterol acceptor.The present work focusses on apoA-I synthesis and its potential role in controlling HDL heterogeneity. The work is based on our previous studies which indicate that hepatic mRNA levels for apoA-I [7] and the rate of apoA-I gene transcription [8] are decreased in hypothyroid rats. The effect of direct injection of 3,3',5-triiodothyronine on apoA-I gene expression has now been examined. The results indicate that increased expression of the apoA-I gene in hyperthyroid rats precedes changes in serum triacylglycerol levels and is associated with significant changes in HDL size and composition.