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Thyroid Hormone Regulates Hepatic Triglyceride Mobilization and Apolipoprotein B Messenger Ribonucleic Acid Editing in a Murine Model of Congenital Hypothyroidism

Departments of Internal Medicine (D.M., S.A., F.N., N.O.D.) and Pharmacology and Molecular Biology (N.O.D.), Washington University, St. Louis, Missouri 63110; and Laboratoire de Biologie Moleculaire et Cellulaire (M.P., J.S.), École Normale Supérieure de Lyon, 69364 Lyon, France

Address all correspondence and requests for reprints to: Nicholas O. Davidson, M.D., Gastroenterology Division, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110. E-mail: nod{at}im.wustl.edu.

Thyroid hormone modulates the expression of numerous genes that in turn regulate lipoprotein metabolism in vivo. We have examined the thyroid hormone-dependent regulation of apolipoprotein B (apoB) RNA editing in a strain of congenitally hypothyroid mice (Pax8^-/-) that lacks thyroid follicular cells. Neonatal Pax8^-/- mice demonstrate an approximately 10-fold increase in hepatic triglyceride content associated with a decrease in hepatic apoB RNA editing. Thyroid hormone administration resulted in hepatic triglyceride mobilization in conjunction with an increase in hepatic, but not intestinal, apoB RNA editing and without changing total apoB RNA abundance. ApoB RNA editing is mediated by a multicomponent enzyme complex whose catalytic core contains two proteins, apobec-1 and apobec-1 complementation factor (ACF). Hepatic ACF mRNA and protein abundance decreased in Pax8^-/- mice, with restoration after thyroid hormone administration, whereas apobec-1 mRNA and protein abundance were unchanged. Immunohistochemical analysis revealed increased staining intensity of ACF within hepatocyte nuclei of treated mice, findings confirmed by Western analysis of isolated nuclei. In vitro RNA editing assays demonstrated that supplementation with recombinant ACF alone restored enzymatic activity of S100 extracts from hypothyroid, Pax8^-/- mice. These data demonstrate that thyroid hormone modulates murine hepatic lipoprotein metabolism in association with tissue-specific effects on apoB RNA editing mediated through alterations in ACF gene expression.

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