Thyroid hormone crosstalk with nuclear receptor signaling in metabolic regulation

Abstract

Thyroid hormone influences diverse metabolic pathways important in lipid and glucose metabolism, lipolysis and regulation of body weight. Recently, it has been recognized that thyroid hormone receptor interacts with transcription factors that predominantly respond to nutrient signals including the peroxisome proliferator-activated receptors, liver X receptor and others. Crosstalk between thyroid hormone signaling and these nutrient responsive factors occurs through a variety of mechanisms: competition for retinoid X receptor heterodimer partners, DNA binding sites and transcriptional cofactors. This review focuses on the mechanisms of interaction of thyroid hormone signaling with other metabolic pathways and the importance of understanding these interactions to develop therapeutic agents for treatment of metabolic disorders, such as dyslipidemias, obesity and diabetes.

Figure 1

Crosstalk between Thyroid Hormone Signaling and Pathways in Cholesterol Metabolism. (i) Cholesterol in the form of low density lipoprotein (LDL) is transported from the liver to peripheral tissues by LDL receptor (LDL-R). (ii) Thyroid hormone receptor (TR) and sterol regulatory element binding protein (SREBP)-2 stimulate LDL-R gene expression and increase cholesterol uptake. SREBP-2 gene expression is stimulated by thyroid hormone signaling and feedback-regulation by sterols. (iii) The excess cholesterol in liver is converted to bile acids, catalyzed by cholesterol 7-hydroxylase (CYP7A1). This bile acid feedback is modulated by multiple nuclear receptors regulating CYP7A1 gene expression. Liganded TR and peroxisome proliferator activated (PPAR)α inhibit, and hepatic nuclear factor (HNF)4α stimulates, CYP7A1 gene expression and bile acid synthesis (thyroid hormone stimulates CYP7A1 expression in mice, see description in text). (iv) Cholesterol efflux in peripheral tissue relies on the ATP-binding-cassette transporter A1 (ABCA1) transporter. Cholesterol is transported by ABCA1 to lipid-poor apolipoprotein A1 (ApoA1) to form nascent high density lipoprotein (HDL). Cholesteryl ester-rich HDL enters the circulation and transports cholesterol back to liver through SRB1 or LDL-R or cholesteryl ester transfer protein (CETP) for disposal. Liver X receptor (LXR) stimulates ABCA1 activity. T3 inhibits LXR-stimulated ABCA1 gene expression by competing for DNA binding sites and for the heterodimer partner retinoid X receptor (RXR). PPARα agonists stimulate cholesterol efflux by increasing expression of LXR. CE-cholesteryl ester, FC-free cholesterol

Figure 2

Crosstalk Between Thyroid Hormone Signaling and Metabolic Pathways in Fatty Acid Synthesis and β-Oxidation. Fatty acid synthesis and oxidation mobilizes glucose and triglycerides stores, important for thermogenesis and energy homeostasis. (i) Fatty acid synthesis is controlled by the rate limiting enzyme acetyl-CoA carboxylase (ACC)1. Thyroid hormone increases ACC1 mRNA expression by directly stimulating the ACC1 promoter that contains a thyroid hormone receptor response element (TRE) and sterol regulating element binding protein response element (SRE). (ii) Liver X receptor (LXR) stimulates fatty acid synthesis by enhancing SREBP-1c gene expression. In the absence of T3, TR competes with LXR for DNA binding and inhibits expression of SREBP-1c. (iii) Peroxisome proliferator-activated receptor (PPAR)α agonist increases fatty acid synthesis by enhancing sterol regulating element binding protein (SREBP) processing enzymes (insig-1 and −2) and SREBP-1c maturation. (iv) Thyroid hormone increases fatty acid oxidation by upregulating expression of the key mitochondrial β-oxidation enzyme, carnityl palmotoyl transferase (CPT)-Iα. PPARα also stimulates expression of CPT-Iα and promotes fatty acid β-oxidation. Omega-3 long-chain fatty acids are ligands for PPARα. PPARα also stimulates Acyl-CoA oxidase (ACO), a rate limiting enzyme in peroxisomal β-oxidation. Unliganded TR can block stimulation of CPT1α and ACO by PPARα competing for limiting retinoid x receptor (RXR) and by binding to the PPRE.