Transcriptional regulation of apolipoprotein A-I gene expression by the nuclear receptor RORalpha

• Published in: The Journal of biological chemistry Vol. 272; no. 36; p. 22401
• Main Authors: Vu-Dac, N. (INSERM, Institut Pasteur de Lille, Lille, France.), Gervois, P, Grotzinger, T, Vos, P. de, Schoonjans, K, Fruchart, J.C, Auwerx, J, Mariani, J, Tedgui, A, Staels, B
• Format: Journal Article
• Language: English
• Published: United States 05.09.1997
• Subjects: ACILTRANSFERASA; ACYLTRANSFERASE; ACYLTRANSFERASES; Animals; Apolipoprotein A-I - genetics; APOPROTEINAS; APOPROTEINE; APOPROTEINS; ARN MENSAJERO; ARN MESSAGER; BINDING SITES; CACO-2 CELLS; CARCINOMA; CARCINOME; CELL CULTURE; Cell Line; CELL LINES; CHLORAMPHENICOL ACETYLTRANSFERASE; Chlorocebus aethiops; CULTIVO DE CELULAS; CULTURE DE CELLULE; DELETIONS; EXPRESION GENICA; EXPRESSION DES GENES; FACTEUR DE TRANSCRIPTION; FACTORES DE TRANSCRIPCION; GENE; GENE EXPRESSION; Gene Expression Regulation; GENES; GENETIC REGULATION; GENETICA; GENETICS; GENETIQUE; Humans; INTESTIN; INTESTINES; INTESTINOS; MEMBRANA MUCOSA; MESSENGER RNA; MICE; MUCOUS MEMBRANE; MUQUEUSE; MUTACION; MUTATION; Promoter Regions, Genetic; PROMOTERS; RAT; RATA; RATON; RATS; Receptors, Cytoplasmic and Nuclear - physiology; Recombinant Proteins - genetics; REPORTER GENES; ROR RESPONSIVE ELEMENT; SMALL INTESTINE; SOURIS; TARGETED MUTAGENESIS; TRANSCRIPCION; TRANSCRIPTION; TRANSCRIPTION FACTORS; Transcription, Genetic
• ISSN: 0021-9258; 1083-351X

Since elevated concentrations of plasma high density lipoprotein (HDL) and its major apolipoprotein (apo), apoA-I, confer protection against atherosclerosis, considerable research efforts have focussed on the identification of factors regulating apoA-I gene expression in an attempt to increase its production. Nuclear receptors are interesting candidates because they are transcription factors whose activity is ligand-dependent. In the present study we identified the orphan receptor RORalpha1 as an activator of apoA-I gene transcription. In apoA-I-expressing intestinal Caco-2 cells, overexpression of the RORalpha1, but not the RORalpha2 or RORalpha3 isoforms, increased rat apoA-I gene transcription. Deletion and site-directed mutagenesis experiments identified a functional ROR-responsive element (RORE) in the rat and mouse apoA-I gene promoters, which overlaps with the TATA box. Gel shift experiments indicated that this RORE binds the RORalpha1 isoform, but not the RORalpha2 or RORalpha3 isoforms. Furthermore, compared with wild type mice, apoA-I mRNA levels were significantly lower in small intestines of staggerer mice homozygous for a deletion in the RORalpha gene. In addition, reverse transcriptase-polymerase chain reaction analysis revealed the expression of RORalpha in small intestinal epithelium and in Caco-2 cells. These data indicate a novel, physiological role for RORalpha1 in the regulation of genes involved in lipid and lipoprotein metabolism and possibly in the development of metabolic diseases, such as atherosclerosis.