Apolipoprotein B mRNA editing is modulated by thyroid hormone analogs but not growth hormone administration in the rat

Recent work has demonstrated that the unique post-transcriptional 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 thyroid 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 B ₁₀₀) 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 27, and 21_s ME transcripts by native T₃, there was a modest induction of the 21, ME transcript (average of 2- to 4-fold) with both T₃ analogs. However, the more potent T₃ analog induced the 27, 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 27, ME transcript, compared to native T₃. Taken together, the data indicate that these synthetic T₃ analogs capitulate several actions of native 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.