Role of CCAAT/enhancer-binding protein, histone acetylation, and coactivator recruitment in the regulation of malic enzyme transcription by thyroid hormone.
ABSTRACT In chick embryo hepatocytes, activation of malic enzyme gene transcription by triiodothyronine (T3) is mediated by a T3 response unit (T3RU) that contains five T3 response elements (T3REs) plus five accessory elements that enhance T3 responsiveness conferred by the T3REs. Results from in vitro binding assays indicate that one of the accessory elements (region F) binds CCAAT/enhancer-binding protein-alpha (C/EBPalpha). Here, we investigated the role of C/EBPalpha in the regulation of malic enzyme transcription by T3. Transfection analyses demonstrated that the stimulation of T3RE function by region F did not require the presence of additional malic enzyme gene promoter sequences. Expression of a dominant negative C/EBP inhibited the ability of region F to stimulate T3 responsiveness. In chromatin immunoprecipitation assays, C/EBPalpha and TR associated with the malic enzyme T3RU in the absence and presence of T3 with the extent of the association being greater in the presence of T3. These observations indicate that C/EBPalpha interacts with TR on the malic enzyme T3RU to enhance T3 regulation of malic enzyme gene transcription. T3 treatment increased the acetylation of histones, decreased the recruitment of nuclear receptor corepressor and increased the recruitment of steroid receptor coactivator-1, CREB binding protein, and the thyroid hormone associated protein/mediator complex at the malic enzyme T3RU. In contrast, T3 treatment had no effect on the acetylation of histones and the recruitment of corepressors and coactivators at the T3RU that mediates the T3 activation of acetyl-CoA carboxylase-alpha gene transcription. We propose that differences between the malic enzyme T3RU and the ACCalpha T3RU in the ability of T3 to modulate histone acetylation and coregulatory protein recruitment are due to differences in the composition of the nuclear receptor complexes that bind these regulatory regions.
Article: Influence of neonatal hypothyroidism on hepatic gene expression and lipid metabolism in adulthood.[show abstract] [hide abstract]
ABSTRACT: Thyroid hormones are required for normal growth and development in mammals. Congenital-neonatal hypothyroidism (CH) has a profound impact on physiology, but its specific influence in liver is less understood. Here, we studied how CH influences the liver gene expression program in adulthood. Pregnant rats were given the antithyroid drug methimazole (MMI) from GD12 until PND30 to induce CH in male offspring. Growth defects due to CH were evident as reductions in body weight and tail length from the second week of life. Once the MMI treatment was discontinued, the feed efficiency increased in CH, and this was accompanied by significant catch-up growth. On PND80, significant reductions in body mass, tail length, and circulating IGF-I levels remained in CH rats. Conversely, the mRNA levels of known GH target genes were significantly upregulated. The serum levels of thyroid hormones, cholesterol, and triglycerides showed no significant differences. In contrast, CH rats showed significant changes in the expression of hepatic genes involved in lipid metabolism, including an increased transcription of PPARα and a reduced expression of genes involved in fatty acid and cholesterol uptake, cellular sterol efflux, triglyceride assembly, bile acid synthesis, and lipogenesis. These changes were associated with a decrease of intrahepatic lipids. Finally, CH rats responded to the onset of hypothyroidism in adulthood with a reduction of serum fatty acids and hepatic cholesteryl esters and to T3 replacement with an enhanced activation of malic enzyme. In summary, we provide in vivo evidence that neonatal hypothyroidism influences the hepatic transcriptional program and tissue sensitivity to hormone treatment in adulthood. This highlights the critical role that a euthyroid state during development plays on normal liver physiology in adulthood.PLoS ONE 01/2012; 7(5):e37386. · 4.09 Impact Factor