Regulation of cholesterol-7α-hydroxylase: BAREly missing a SHP

Cholesterol-7 � -hydroxylase (CYP7A1) regulates the pathway through which cholesterol is converted into bile acids. The unique detergent properties of bile acids are essential for the digestion and intestinal absorption of hy- drophobic nutrients. Bile acids have potent toxic properties (e.g., membrane disruption) and there are a plethora of mechanisms to limit their accumulation in blood and tis- sues. The discovery of farnesoid X receptor (FXR), the nu- clear receptor activated specifically by bile acids, has opened new insights into these mechanisms. Bile acid acti- vation of FXR has been shown to repress the expression of CYP7A1 via increasing the expression of small heterodimer partner (SHP), a non-DNA binding protein. The increased abundance of SHP causes it to associate with liver receptor homolog (LRH)-1, an obligate factor required for transcrip- tion of CYP7A1. Recent studies show there is an "FXR/ SHP-independent" mechanism that also represses CYP7A1 expression. This "FXR/SHP-independent" pathway in- volves the interaction of bile acids with liver macrophages (i.e., Kupffer cells), which induces the expression, and se- cretion of cytokines. These inflammatory cytokines, which include tumor necrosis factorand interleukin-1 � , act upon liver parenchymal cells causing a rapid repression of the CYP7A1 gene. —Davis, R. A., J. H. Miyake, T. Y. Hui, and N. J. Spann. Regulation of cholesterol-7 � -hydroxylase: BAREly missing a SHP. J. Lipid Res. 2002. 43: 533-543.