The net effects of thyroid hormone are brought about by the changes it causes in the expression of T₃-responsive genes in target tissues. For instance, the increase in low-density lipoprotein (LDL) cholesterol that occurs in hypothyroid patients can be attributed to a decrease in LDL–receptor protein expression since the gene for this protein is sensitive to thyroid hormone. The presence of thyroid hormone is signaled by the cell through nuclear thyroid hormone receptors (TRs). The TRs are members of the so-called nuclear receptor superfamily, of which the steroid, vitamin D, and retinoic acid receptors are also members. These receptors influence gene expression by binding to specific DNA elements as dimers. TR can bind as a homodimer (two identical monomers) or as a heterodimer (two different monomers) to these specific DNA elements, called thyroid response elements (TREs), located in the promoter region of T₃-responsive genes. A number of isoforms of the TRs are known that derive from two different genes and that are expressed at different relative levels in different tissues (Fig. 1). Furthermore, a number of different TREs can bind the receptors, sometimes in specific combinations, so there is a plethora of regulatory possibilities.