My long-term goal is to understand the contribution of sulfation to BA physiology and toxicology. The objective here, which is my first step in pursuit of that goal, is to determine which cytosolic sulfotransferases (Sults) are pharmacologically inducible and responsible for BA-sulfation. My central hypothesis is that pharmacologic activation of CAR, PXR and LXR is capable of inducing multiple mouse Sults and consequently increasing BA-sulfate formation in mouse liver. Therefore, the rationale for the proposed research is that, once it is known which mouse Sults are responsible for the formation of each BA-sulfate, Sults can be approached as legitimate drug targets for the treatment of liver diseases. I plan to test my central hypothesis and, thereby, accomplish the objective of this application by pursuing the following two specific aims: 1. Determine whether CAR, PXR or LXR activation is the most effective at increasing sulfation of BAs. Mice will be treated with pharmacologic activators of CAR, PXR, and LXR in order to determine the effect of CAR, PXR, and LXR activation on BA-sulfate formation. Whereas it is known that activation of these three nuclear receptors is capable of increasing mRNA levels of Sults, it is not known whether the activation leads to increased BA sulfation. 2. Determine which Sults are responsible for 3-OH- and 7-OH-sulfation of BAs observed in vivo. We will express and purify mouse Sults to determine their capacity to sulfate various BAs at the 3-OH and 7-OH position. Determining which Sults are responsible for formation of each BA-sulfate will inform us of which Sults need to be targeted to protect against BA-induced hepatotoxicity. Knowledge of the BA-sulfation pathways responsible for 3-OH- and 7-OH-sulfation will reveal potential drug targets for the treatment of liver diseases. With respect to expected outcomes, the work proposed in aims 1 and 2 is expected to confirm (1) that induction of Sults in mouse liver results in enhanced formation of BA sulfates, and (2) which Sults are responsible for BA-sulfation. Such results are expected to have a valuable positive impact because each will inform us of which Sults are most critical to BA homeostasis. Identification of each of the Sults responsible for BA sulfation may be of tremendous utility in developing novel therapies for the treatment of liver diseases. The research proposed in this application is innovative, in our opinion, because the testing of our central hypothesis is possible because of a UPLC-MS/MS method recently developed in our laboratory that will enable us to identify the individual Sult(s) responsible for the sulfation at the 3-OH and 7-OH positions of BAs.
The proposed research is relevant to public health because it seeks to address questions regarding bile acid sulfation that may be of tremendous utility in developing novel therapies for the treatment of liver diseases. Thus, the proposed research is relevant to the part of the NIH's misson that pertains to fostering innovative research strategies and their applications as a basis for ultimately protecting and improving health.
|Lickteig, Andrew J; Csanaky, Iván L; Pratt-Hyatt, Matthew et al. (2016) Activation of Constitutive Androstane Receptor (CAR) in Mice Results in Maintained Biliary Excretion of Bile Acids Despite a Marked Decrease of Bile Acids in Liver. Toxicol Sci 151:403-18|