Nitta M, Ku S, Brown C, Okamoto A Y, Shan B
Biology Department, Tularik Inc., Two Corporate Drive, South San Francisco, CA 94080, USA.
Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):6660-5. doi: 10.1073/pnas.96.12.6660.
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.
胆固醇7α-羟化酶是胆固醇代谢为胆汁酸途径中的首个限速酶。编码胆固醇7α-羟化酶的基因CYP7A仅在肝脏中表达。仓鼠中CYP7A的过表达导致血清胆固醇水平降低，这表明该酶在胆固醇稳态中起核心作用。在此，我们报告了一种与人类CYP7A基因启动子结合的肝脏特异性转录因子的鉴定。我们将该因子命名为CPF，即CYP7A启动子结合因子。在瞬时转染实验中，CYP7A启动子内CPF结合位点的突变消除了该基因的肝脏特异性表达。克隆了编码CPF的cDNA，并鉴定其为果蝇孤儿核受体腹节基因F1（Ftz-F1）的人类同源物。CPF表达质粒与CYP7A报告基因的共转染导致CYP7A指导转录的特异性诱导。这些观察结果表明CPF是肝脏中人类CYP7A基因表达的关键调节因子。
