Thyroid Hormone Receptor β (TRβ) and Liver X Receptor (LXR) Regulate Carbohydrate-response Element-binding Protein (ChREBP) Expression in a Tissue-selective Manner

Karine Gauthier,Cyrielle Billon,Marie Bissler,Michel Beylot,Jean-Marc Lobaccaro,Jean-Marc Vanacker,Jacques Samarut

doi:10.1074/jbc.m110.146241

Abstract

Thyroid hormone (TR) and liver X (LXR) receptors are transcription factors involved in lipogenesis. Both receptors recognize the same consensus DNA-response element in vitro. It was previously shown that their signaling pathways interact in the control of cholesterol elimination in the liver. In the present study, carbohydrate-response element-binding protein (ChREBP), a major transcription factor controlling the activation of glucose-induced lipogenesis in liver, is characterized as a direct target of thyroid hormones (TH) in liver and white adipose tissue (WAT), the two main lipogenic tissues in mice. Using genetic and molecular approaches, ChREBP is shown to be specifically regulated by TRbeta but not by TRalpha in vivo, even in WAT where both TR isoforms are expressed. However, this isotype specificity is not found in vitro. This TRbeta specific regulation correlates with the loss of TH-induced lipogenesis in TRbeta(-/-) mice. Fasting/refeeding experiments show that TRbeta is not required for the activation of ChREBP expression particularly marked in WAT following refeeding. However, TH can stimulate ChREBP expression in WAT even under fasting conditions, suggesting completely independent pathways. Because ChREBP has been described as an LXR target, the interaction of LXR and TRbeta in ChREBP regulation was assayed both in vitro and in vivo. Each receptor recognizes a different response element on the ChREBP promoter, located only 8 bp apart. There is a cross-talk between LXR and TRbeta signaling on the ChREBP promoter in liver but not in WAT where LXR does not regulate ChREBP expression. The molecular basis for this cross-talk has been determined in in vitro systems.

Highlights

Trations induce this process, converting the excess energy into triglycerides, a more relevant molecule for storage purposes
Thyroid hormones (TH) up-regulate lipogenesis in liver, but their roles in white adipose tissue (WAT) are controversial (9 –11). Their actions are mediated by the TR␣ and TR␤ nuclear receptors, which act as transcription factors by binding to specific TH-response elements (TRE) as homodimers or heterodimers with the nuclear receptor RXR [12]
This effect is TR␤, but not TR␣, dependent, both TR isoforms are strongly expressed in WAT, whereas in vitro, both isoforms can drive the expression of a reporter gene downstream of the carbohydrate-response element-binding protein (ChREBP) promoter and bind to the same response element

Summary

Introduction

Trations induce this process, converting the excess energy into triglycerides, a more relevant molecule for storage purposes. This effect is TR␤-, but not TR␣-, dependent, both TR isoforms are strongly expressed in WAT, whereas in vitro, both isoforms can drive the expression of a reporter gene downstream of the ChREBP promoter and bind to the same response element.

Results

Conclusion