“Don't Know Much Bile-ology”

terol is degraded into bile acids, and the rate-limiting Ajay Chawla, Enrique Saez, and Ronald M. Evans* Howard Hughes Medical Institute step for the neutral bile biosynthesis pathway is cataThe Salk Institute for Biological Sciences lyzed by the cytochrome P450 cholesterol 7a-hydroxy10010 N. Torrey Pines Road lase or CYP7A1 (Russell and Setchell, 1992). Regulation La Jolla, California 92037 of CYP7A1 levels is known to occur primarily at the transcriptional level and is modulated by the relative ratio of cholesterol to bile acids in the liver. A minireview describing the pathways of cholesterol catabolism and A central aspect of lipid homeostasis in vertebrates is their regulation by nuclear receptors was published last the acquisition, synthesis, and metabolism of cholesyear in Cell (Russell, 1999). Here, we review work pubterol. As mediators of organ physiology, nuclear horlished recently in Cell and Molecular Cell that establishes mone receptors and other proteins such as the SREBPs a specific role for the nuclear receptor FXR in this proare believed to play a key role in these processes by cess and in the repression of the CYP7A1 gene. This controlling the transcription of genes encoding apolipowork enhances our understanding of how cholesterol proteins, transporters, as well as synthetic and catabolic catabolism is regulated by nuclear receptors, and thus enzymes (Brown and Goldstein, 1997). Since their initial has important implications for future drug development discovery, orphan nuclear receptors have been susin the treatment of hypercholesterolemia and cholepected to represent critical components of lipid metabostasis. lism; however, deciphering their precise roles has repreRole of FXR in Bile Acid Homeostasis sented a major challenge (Blumberg and Evans, 1998; The metabolic regulation of CYP7A1 has been an active Giguere et al., 1988). Particularly vexing is understandarea of research for decades because of its role in choing the molecular links that make physiology integrative. lesterol metabolism (Russell and Setchell, 1992). Two The liver is the central organ for regulation of cholespapers in the September issue of Molecular Cell use terol homeostasis. Integrating pathways of synthesis different approaches to shed light on how bile acids and degradation, it provides cells with the cholesterol repress the transcription of the CYP7A1 gene, the rateneeded for cellular growth, while preventing its pathologic accumulation. The majority of any excess choleslimiting step in their synthesis (Goodwin et al., 2000; Lu