RESUMEN
Bile acids are essential for the solubilization and transport of dietary lipids and are the major products of cholesterol catabolism. Results presented here show that bile acids are physiological ligands for the farnesoid X receptor (FXR), an orphan nuclear receptor. When bound to bile acids, FXR repressed transcription of the gene encoding cholesterol 7alpha-hydroxylase, which is the rate-limiting enzyme in bile acid synthesis, and activated the gene encoding intestinal bile acid-binding protein, which is a candidate bile acid transporter. These results demonstrate a mechanism by which bile acids transcriptionally regulate their biosynthesis and enterohepatic transport.
Asunto(s)
Ácidos y Sales Biliares/metabolismo , Proteínas Portadoras/genética , Ácido Quenodesoxicólico/metabolismo , Colesterol 7-alfa-Hidroxilasa/genética , Proteínas de Unión al ADN/metabolismo , Hidroxiesteroide Deshidrogenasas , Glicoproteínas de Membrana , Transportadores de Anión Orgánico Sodio-Dependiente , Receptores Citoplasmáticos y Nucleares/metabolismo , Simportadores , Factores de Transcripción/metabolismo , Animales , Ácidos y Sales Biliares/biosíntesis , Transporte Biológico , Proteínas Portadoras/metabolismo , Línea Celular , Colesterol/metabolismo , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/genética , Regulación de la Expresión Génica , Histona Acetiltransferasas , Homeostasis , Humanos , Ligandos , Hígado/metabolismo , Ratones , Coactivador 1 de Receptor Nuclear , Receptores Citoplasmáticos y Nucleares/química , Receptores Citoplasmáticos y Nucleares/genética , Factores de Transcripción/química , Factores de Transcripción/genética , Transfección , Células Tumorales CultivadasRESUMEN
Bile acid synthesis is a major pathway for cholesterol disposal and thus represents a potential therapeutic target pathway for the treatment of hypercholesterolemia. Recently, the nuclear farnesoid X receptor (FXR) was identified as a bile acid receptor and biological sensor for the regulation of bile acid biosynthesis. FXR was shown to regulate cholesterol metabolism in two ways: (1) chenodeoxycholic acid (CDCA), a primary bile acid, binds directly to and activates FXR, which then mediates the feedback suppression by bile acids of cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid biosynthesis from cholesterol; and (2) FXR participates in the activation of intestinal bile acid binding protein (IBABP), which is involved in the enterohepatic circulation of bile acids. Thus FXR constitutes a potential therapeutic target that can be modulated to enhance the removal of cholesterol from the body.
Asunto(s)
Ácidos y Sales Biliares/metabolismo , Proteínas de Unión al ADN/metabolismo , Receptores de Superficie Celular/metabolismo , Factores de Transcripción/metabolismo , Animales , Bilis/metabolismo , Colesterol/metabolismo , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/genética , Regulación de la Expresión Génica/fisiología , Humanos , Ligandos , Receptores de Superficie Celular/antagonistas & inhibidores , Receptores de Superficie Celular/genética , Receptores Citoplasmáticos y Nucleares , Relación Estructura-Actividad , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/genéticaRESUMEN
Cholesterol 7alpha-hydroxylase is the first and rate-limiting enzyme in a pathway through which cholesterol is metabolized to bile acids. The gene encoding cholesterol 7alpha-hydroxylase, CYP7A, is expressed exclusively in the liver. Overexpression of CYP7A in hamsters results in a reduction of serum cholesterol levels, suggesting that the enzyme plays a central role in cholesterol homeostasis. Here, we report the identification of a hepatic-specific transcription factor that binds to the promoter of the human CYP7A gene. We designate this factor CPF, for CYP7A promoter binding factor. Mutation of the CPF binding site within the CYP7A promoter abolished hepatic-specific expression of the gene in transient transfection assays. A cDNA encoding CPF was cloned and identified as a human homolog of the Drosophila orphan nuclear receptor fushi tarazu F1 (Ftz-F1). Cotransfection of a CPF expression plasmid and a CYP7A reporter gene resulted in specific induction of CYP7A-directed transcription. These observations suggest that CPF is a key regulator of human CYP7A gene expression in the liver.