Thyroid hormone receptor beta (TRbeta) and liver X receptor (LXR) regulate carbohydrate-response element-binding protein (ChREBP) expression in a tissue-selective manner.
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.
Gauthier
Karine
K
Institut de Génomique Fonctionnelle de Lyon, Université Lyon 1, CNRS, INRA, Ecole Normale Supérieure de Lyon, 46 allée d'Italie, 69364 Lyon, France. kgauthie@ens-lyon.fr
Billon
Cyrielle
C
Bissler
Marie
M
Beylot
Michel
M
Lobaccaro
Jean-Marc
JM
Vanacker
Jean-Marc
JM
Samarut
Jacques
J
D041721:3T3-L1 Cells; D052438:Adipocytes, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D050155:Lipogenesis / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009752:Nutritional Status; D009928:Organ Specificity; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D037042:Thyroid Hormone Receptors beta / Q000378:metabolism*; D013963:Thyroid Hormones / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D000071518:Liver X Receptors; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D057093:Orphan Nuclear Receptors; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones; D014157:Transcription Factors