Distinct Dysregulation of Lipid Metabolism by Unliganded Thyroid Hormone Receptor Isoforms

Thyroid hormone receptors (TRs) play critical roles in energy homeostasis. To understand the role of TRs in lipid homeostasis in vivo, we adopted the loss-of-function approach by creating knock-in mutant mice with targeted mutation in the TR alpha gene (TR alpha 1PV mouse) or TR alpha gene (TR beta PV mouse). The PV mutation, identified in a patient with resistance to thyroid hormone, exhibits potent dominant-negative activity. Here we show that in contrast to TR alpha 1PV mouse, TR beta PV mice exhibited no significant reduction in WAT but had significant increases in serum free fatty acids and total triglycerides. Moreover, the liver of TR beta PV mice was markedly increased (33%) with excess lipid accumulation, but the liver mass of TR alpha 1PV mouse was decreased (23%) with paucity of lipids. These results indicate that apo-TR beta and apo-TR alpha 1 exerted distinct abnormalities in lipid metabolism. Further biochemical analyses indicate that increased lipogenic enzyme expression, activated peroxisome proliferator-activated receptor gamma(Ppar gamma) signaling, and decreased fatty acid beta-oxidation activity contributed to the adipogenic steatosis and lipid accumulation in the liver of TR beta PV mice. In contrast, the expression of lipogenic enzymes and Ppar gamma was decreased in the liver of TR alpha 1PV mice. These results suggest that the regulation of genes critical for lipid metabolism by TRs in the liver is isoform dependent. These results indicate that apo-TR beta and apo-TR alpha 1 had different effects on lipid metabolism and that both TR isoforms contribute to the pathogenesis of lipid metabolism in hypothyroidism. (Molecular Endocrinology 23: 308-315, 2009)