Patterns of liver gene expression governed by TRβ

Several metabolic processes in the liver are regulated by thyroid hormone (T-3). Gene expression profiles of livers from normal and TRbeta-deficient mouse strains should allow the classification of rapid and sustained effects of T-3 as well as identification of target genes that are dependent on TRbeta. The immediate and long-term T-3 regulation of about 4000 genes in livers from hypo- and hyperthyroid wild-type and TRbeta-deficient mice was analyzed using cDNA microarrays. T-3 was found to regulate more than 200 genes, and among these, more than 100 were previously not described. Sixty percent of all these genes show dependence on the TRbeta gene for T-3 regulation, indicating that TRalpha1 may have previously unknown functions in the liver. Analysis of the gene expression patterns showed a clear functional distinction between rapid (2 h) actions of T-3 and late effects, seen after 5 d of sustained T-3 treatment. Many metabolic actions were rapidly executed, whereas effects on mitochondrial function, for example, were seen after the sustained T-3 treatment. As compared with wild-type controls, TRbeta-/- mice exhibited elevated expression of some target genes and reduced levels of others, indicating that both direct and indirect gene regulation by TRs in liver is complex and involves both ligand-dependent and -independent actions by the major TR isoforms.