Thyroid hormone metabolism and action in different cell types. (a) Hepatocytes (which express D1), as a model for cells that do not express D2. D1 converts plasma T4 to T3, but this T3 does not have direct access to the cell nucleus. Plasma T3 enters the nucleus. In the euthyroid state, TRs are about 50% T3-occupied and target genes are induced proportionately. (b) BAT, as a model for tissues that express D2. Plasma T3 enters the nucleus. In addition, the ER enzyme D2 converts T4 to T3, which has direct access to the nucleus, resulting in a high level of TR occupancy by T3. Target genes are induced proportionately. D2 is regulated by metabolic perturbations, e.g., cold exposure (via norepinephrine) in BAT. The catalytic activity of D2 stimulates its ubiquitination and potential degradation in proteasomes. However, the VDUs can prevent degradation and recover enzyme activity by deubiquitinating Ub-D2. In BAT, VDU1 itself is induced by cold exposure, via norepinephrine. In some tissues, VDUs are ubiquitinated by pVHL and degraded, but this has not been studied in BAT. The retinoid X receptor (RXR) is the dimerization partner for TR.