Thyroid Hormone Receptor Regulation of Cholesterol and Lipid Metabolism

Thyroid hormone receptor (TR) activation affects numerous metabolic processes involved in lipid and glucose metabolism, with implications for diseases such as obesity, diabetes, and hyperlipidemia. Thyroid hormone and synthetic TR agonists are known to decrease serum lipids and induce fat loss. Here we investigate the effects of TR agonists on lipid homeostasis in the liver and adipose tissue. TR agonists lower serum cholesterol levels in rodents, monkeys, and humans. While it is clear that TR activation reduces serum cholesterol, the mechanism behind this effect is less apparent. Although TR agonists have been reported to affect several pathways involved in cholesterol metabolism, the most notable rationale has been that thyroid hormones stimulate expression of the LDL receptor (LDLR). Here we show TR activation can markedly reduce serum cholesterol in mice devoid of LDLR by inducing Cyp7a1 expression and stimulating the conversion and excretion of cholesterol as bile acids. Thus, TR agonists may represent a promising therapeutic to treat hypercholesterolemia disorders for which LDLR induction is not fully effective. Thyroid hormones have long been known to stimulate basal metabolic rate and elicit thermogenesis, effects generally attributed to the activation of brown adipose tissue (BAT). However, the relationship between TR activation and thermogenesis is complex and not fully resolved. Here we show that thyroid hormone and the TR agonist GC-1 induce a BAT-like program of adaptive thermogenesis and uncoupled respiration in subcutaneous white adipose tissue (WAT), which appears to directly mediate an increase in metabolism and marked fat loss. The TR mediated conversion of white to beige fat, an action accompanied by striking anti-diabetic and anti-obesity properties, may represent an unrecognized component of TR-mediated thermogenesis and demonstrates the profound pharmacological potential of beiging of WAT. In conclusion, we have shown that TR activation in the liver reduces serum cholesterol independent of the LDLR via the induction of hepatic Cyp7a1 and that TR activation in WAT elicits a functional conversion of white to brown fat. These data show the TR activation has beneficial effects on lipid homeostasis in the liver and adipose tissue and may suggest an important strategy to combat metabolic diseases.Biology and Biochemistry, Department o