Nuclear Orphan Receptors Control Cholesterol Catabolism

Enterocytes protect themselves from the detergent actions of intracellular bile acids by expressing the ileal bile acid binding protein (encoded by the IBABP gene), which facilitates the movement of the detergents across the cell and their secretion into the portal circulation. Over the last three decades, much progress has been When they reach the liver, the bile acids are taken up made in understanding the mechanisms and regulation by a transporter on the apical surface of the hepatocyte, of the cholesterol supply pathways that cells and tissues and thereafter they are secreted into the bile duct to use to sate their demands for this essential membrane begin another round of the enterohepatic cycle. component. But how does the body get rid of excess Bile acids thus perform several functions in lipid physi-cholesterol and by what means is the catabolic process ology. First, their synthesis provides a disposal mecha-regulated? These questions are of medical as well as nism to counterbalance the cholesterol synthesis path-scientific importance because controlled elimination is way and allow homeostasis to be achieved. Second, one of the body's chief defenses against cholesterol their detergent actions are essential within the intestine accumulation and consequent heart attacks. Several for the uptake of hydrophobic nutrients like fat-soluble recent papers address the essence of these questions vitamins, and within the liver for the solubilization of and reveal potential physiological roles for three nuclear metabolites like bilirubin. Third, as detailed below, inter-orphan receptors, the LXR␣ (or more properly NR1H2; mediates and endproducts of the bile acid pathway reg-Nuclear Receptors Nomenclature Committee, 1999), ulate the expression of genes that synthesize choles-CPF (NR5A2), and FXR (NR1H4) proteins, in controlling terol, fatty acids, and bile acids themselves. the conversion of cholesterol into its bulk catabolic Pathways of Bile Acid Synthesis products, namely, the bile acids. In the early 1940s Konrad Bloch fed radiolabeled choles-Included in this body of work is a paper in the May terol to dogs and observed its conversion to polar me-issue of Molecular Cell in which Wang et al. (1999) show tabolites that were excreted in the stool. These were that chenodeoxycholate, a bile acid derived from cho-identified as bile acids, which generally have three fewer lesterol, interacts with a nuclear hormone receptor, FXR, carbon atoms than cholesterol. They also have multiple to suppress transcription from a reporter gene. In two papers appearing in Science, Makishima et al. (1999) and Parks et …