TRANSCRIPTIONAL REGULATION OF ALDO-KETO REDUCTASE 1D1

Abstract

Bile acids are physiological detergents and surfactants with recently identified roles as signaling hormones. Maintenance of physiologically normal bile acids levels is fundamentally important as a deregulation within the bile acid synthesis pathway has the potential to result in an unbalanced bile acid pool. This may result in any number of pathological down stream effects and can exacerbate various diseases and disorders. Chenodeoxycholic acid (CDCA) and cholic acid (CA) are two major primary bile acids in humans with CDCA being more hydrophobic and toxic than CA. Aldo-keto reductase 1D1 (AKR1D1) and 12-alpha-hydroxylase (CYP8B1) are the two key enzymes responsible for the synthesis of CDCA and CA, respectively. It remains largely unknown how AKR1D1 and CYP8B1 are regulated to maintain homeostatic CDCA and CA concentrations under physiological conditions. Likewise, little is known regarding the regulation of their synthesis under pathological conditions, or the mechanisms by which this regulation occurs. To date, much focus has been on CYP8B1 expression as the key regulator of bile acid synthesis, and also as the determining factor for the CDCA to CA ratio within the bile acid pool. We hypothesize that due to the increased toxicity associated with elevated CDCA concentrations, combined the knowledge that CDCA is a potent ligand for various signaling pathways, the liver is consistently altering AKR1D1 expression, and not CYP8B1, in an effort to maintain physiologically normal liver function. Further knowledge pertaining to the regulation of individual primary bile acids may shed light on novel mechanisms by which various disorders and diseases, which are attributed to bile acid dysregulation, can be treated or prevented. For example, it has been established that the CDCA composition of the bile acid pool is lower in patients with diabetes; however, the mechanism by which this occurs is unclear. Understanding the role of bile acid synthesis in diabetic models may identify a mechanism by which CDCA production is being regulated. Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer. It has been identified that high concentrations of CDCA are toxic to the hepatocytes and can have carcinogenic effects; therefore a better elucidation of the regulation of CDCA production may prove important for prevention or progression of HCC. Intrahepatic cholestasis of pregnancy (ICP) is a disorder that occurs within the third trimester of pregnancy as a result of elevated bile acid levels. Although AKR1D1 expression is known to increase during pregnancy, the role of AKR1D1 in