NR4A nuclear receptors mediate carnitine palmitoyltransferase 1A gene expression by the rexinoid HX600.
Retinoid X receptors (RXRs) are members of the nuclear receptor superfamily and can be activated by 9-cis retinoic acid (9CRA). RXRs form homodimers and heterodimers with other nuclear receptors such as the retinoic acid receptor and NR4 subfamily nuclear receptors, Nur77 and NURR1. Potential physiological roles of the Nur77-RXR and NURR1-RXR heterodimers have not been elucidated. In this study, we identified a gene regulated by these heterodimers utilizing HX600, a selective RXR agonist for Nur77-RXR and NURR1-RXR. While 9CRA induced many genes, including RAR-target genes, HX600 effectively induced only carnitine palmitoyltransferase 1A (CPT1A) in human teratocarcinoma NT2/D1 cells, which express RXRα, Nur77 and NURR1. HX600 also increased CPT1A expression in human embryonic kidney (HEK) 293 cells and hepatocyte-derived HepG2 cells. Although HX600 induced CPT1A less effectively than 9CRA, overexpression of Nur77 or NURR1 increased the HX600 response to levels similar to 9CRA in NT2/D1 and HEK293 cells. A dominant-negative form of Nur77 or NURR1 repressed the induction of CPT1A by HX600. A protein synthesis inhibitor did not alter HX600-dependent CPT1A induction. Thus, the rexinoid HX600 directly induces expression of CPT1A through a Nur77 or NURR1-mediated mechanism. CPT1A, a gene involved in fatty acid β-oxidation, could be a target of RXR-NR4 receptor heterodimers.
Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.
Michiyasu
M
Ishizawa
Hiroyuki
H
Kagechika
Makoto
M
Makishima
D000077556:Alitretinoin; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase; D045744:Cell Line, Tumor; D003984:Dibenzazepines / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization; D051381:Rats; D047488:Retinoid X Receptors / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology
D003984:Dibenzazepines; C539821:NR4A1 protein, human; C539882:NR4A2 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D047488:Retinoid X Receptors; C104181:HX 600; D000077556:Alitretinoin; D014212:Tretinoin; D002334:Carnitine O-Palmitoyltransferase