Role of thyroid hormone in the expression of apolipoprotein A-IV and C-III genes in rat liver.

The genes coding for apolipoproteins A-I, C-III, and A-IV are closely linked to one another in the rat genome. Thyroid hormone stimulates apoA-I expression in rat liver by an unusual mechanism that enhances the maturation of mRNA. This hormone also increases apoA-IV mRNA abundance by a mechanism not yet studied, and its role in the expression of apoC-III has not been defined but may be of relevance to the metabolism of triglyceride-rich lipoproteins. We therefore measured the transcriptional activity of the apoA-IV and apoC-III genes and the abundance of their nuclear RNA and total cellular mRNA in livers of control rats and rats made hyper- and hypothyroid. After a single receptor-saturating dose of triiodothyronine (3 mg/100 g body weight), apoA-IV gene transcription increased at 20 min and reached a maximum of 260% of control at 6 h. Increases of transcription were reflected in increases of nuclear and total apoA-IV mRNA levels. ApoC-III gene transcription was temporarily increased to 160% at 2 h without changes in the abundance of its nuclear or total mRNA over 24 h. Lower hormone doses (20-500 micrograms/100 g body weight) stimulated apoA-IV mRNA transcription as well, but tended to reduce transcription from the apoC-III gene. Upon chronic administration of thyroid hormone, apoA-IV transcription decreased to 55% and nuclear apoA-IV RNA levels to 87% of control. However, total cellular apoA-IV mRNA levels increased to 279% of control, implying stabilization of mRNA in the cytoplasm. ApoC-III transcription decreased to 28% of control, but abundance of nuclear and total cellular apoC-III mRNA was reduced to a lesser extent. In hypothyroid rats, apoA-IV gene expression was decreased fourfold at the transcriptional level. In contrast, apoC-III gene transcription increased to 178% of control, but the abundance of nuclear and total cellular apoC-III mRNA did not differ from control rats. Thus, thyroid hormone affects the abundance of apoA-IV mRNA by changing its synthesis and its rate of degradation and enhances the efficiency of apoC-III mRNA maturation, thereby blunting the net effect of altered mRNA synthesis on mRNA abundance.