Apolipoprotein B mRNA Editing is Modulated by Thyroid Hormone Analogs but not Growth Hormone Administration in the Rat

Abstract

Recent work has demonstrated that the unique posttranscriptional editing reaction which modifies mammalian apolipoprotein (apo) B100 mRNA, producing an in-frame stop codon in the modified (apo B48) transcript, is modulated in vivo in the rat liver by thryoid hormone (T3). We now report the results of studies undertaken to examine the effects of two synthetic T3 analogs and GH on apo B gene expression together with their effects on hepatic apo A-I, A-IV, C-III, and malic enzyme (ME)mRNAs. The T3 analogs were previously shown to exhibit similar binding to the hepatic nuclear T3 receptor (50% and 38% of native T3) but differing biopotency (18 and <3% of native T3). Apo B100 mRNA editing, determined by differential hybridization of polymerase chain reaction amplified apo B cDNA, demonstrated 50-56% unmodified (apo B100) mRNA in control and hypothyroid animals and this proportion was unaltered by GH (61% B100 mRNA), despite a reduction in apo B100 synthesis. Both T3 analogs altered apo B mRNA editing (12-16% B100 mRNA) and no apo B100 synthesis was detectable in vivo. Additionally, both T3 analogs produced a 4- to 10-fold induction in hepatic apo A-I and A-IV mRNA abundance, similar to the effects of native T3. GH produced no alteration in apo A-I or A-IV mRNA abundance and neither T3 analog, GH, or native T3 produced a change in apo C III mRNA abundance. Finally, in contrast to the greater than 20-fold induction of both the 27s and 21s ME transcripts by native T3, there was a modest induction of the 21s ME transcript (average of 2- to 4-fold) with both T3 analogs. However, the more potent T3 analog induced the 27s ME transcript to a variable extent (range, 5-100% of native T3) while the less potent analog consistently produced less than 10% induction of the 27s ME transcript, compared to native T3. Taken together, the data indicate that these synthetic T3 analogs capitulate several actions of several T3 on hepatic apo gene expression in the rat but exhibit divergence in relation to another class of T3-responsive genes involved in hepatic lipogenesis.