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

Gastroenterology Section, Department of Medicine, University of Chicago Chicago, Illinois 60637

Address requests for reprints to: Dr. Nicholas O. Davidson, Gastroenterology Section, Box 400, Department of Medicine, University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois 60637.

Abstract

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 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 27_s and 218 ME transcripts by native T₃, there was a modest induction of the 21_s ME transcript (average of 2- to 4-fold) with both T₃ analogs. However, the more potent T₃ analog induced the 27_s 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_s 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.

Received for publication December 18, 1990. Revision received February 12, 1990. Accepted for publication February 15, 1990.

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