Bile in the Brain? A Role for Bile Acids in the Central Nervous System

Bile acids were classically viewed as detergents whose main function is to aid in the breakdown of dietary lipids. This is achieved by the formation of mixed micelles with cholesterol and other phospholipids [1]. It is now greatly appreciated that bile acids are more complex than mere detergents, and should actually be viewed as steroid hormones. Like many other steroid hormones such as neurosteroids and glucocorticoids, bile acids are synthesized from the conversion of cholesterol to various bile acids. The “classical pathway” of bile acid synthesis is achieved through the enzymatic activity of the cytochrome P450 family of proteins, namely cholesterol 7α-hydroxylase (Cyp7a1), which is responsible for the 7α-hydroxylation of cholesterol [2]. Historically, bile acid synthesis has been thought to occur solely in the liver, as Cyp7a1 is a liver-specific enzyme, however, an alternative or “acidic pathway” was discovered which starts with the side chain 27-hydroxylation catalyzed by Cyp27a1 [3]. Interestingly, Cyp27a1 is expressed in an array of extrahepatic tissues such as kidney [4], immune cells [5], and the brain [6] and mutations in the Cyp27a1 gene has been shown to underlie the sterol storage disorder cerebrotendinous xanthomatosis, which leads to cholesterol accumulation in the brain and neurological dysfunction [6]. The development of neurological dysfunction by the mutation of a key enzyme in bile acid biosynthesis poses the question of whether bile acids (or their intermediaries) play a physiological role in the brain under homeostatic conditions. It is now well respected that during conditions of liver dysfunction such as cholestatic liver disease (primary sclerosing cholangitis or primary biliary cirrhosis) bile acids are dramatically increased in the circulation [7] and can gain access to brain [8]. Controversy still remains however, as to whether bile acids are present in the brain and play a physiological role in a non-diseased state.