Role of Kynurenine- AhR Signals in Cholestatic Liver Injury - Project Summary/Abstract Cholestatic liver disease results from dysregulated bile acids (BAs) production and impaired bile flow, leading to toxic BAs accumulation and subsequent liver injury. Excessive hydrophobic BAs like lithocholic acid (LCA) are particularly implicated in liver damage by inducing excessive reactive oxygen species (ROS) production and impairing mitochondrial function, culminating in hepatocyte death and inflammatory responses. Thus, understanding how high BA stress regulates ROS production and mitochondrial function is crucial. The Aryl hydrocarbon receptor (AHR), a liver-abundant transcription factor, plays a pivotal role in biological processes, including xenobiotic metabolism. My recent findings underscore its importance in maintaining hepatic mitochondrial homeostasis. AHR inhibition impairs mitochondrial function and increases mitochondrial ROS levels due to a defective mitophagy process, while AHR activation by its endogenous agonist kynurenine (Kyn) restores mitochondrial function. Kyn is mainly synthesized from tryptophan by the kynurenine pathway (KP), which is mainly mediated by tryptophan 2,3-dioxygenase (TDO2) in the liver. However, the functional importance of the KP and AHR regulation in cholestatic liver injury remains unexplored. Interestingly, my preliminary study identified that AHR activity and transcription levels of KP enzymes were suppressed in cholestasis models. Notably, AHR activation reduced ROS production, alleviated hepatocyte damage, and inhibited inflammatory signaling. These findings strongly suggest the pivotal role of the Kyn-AHR pathway in cholestatic liver injury. My central hypothesis is that AHR activation regulates ROS accumulation and mitochondrial function, and inflammation against cholestatic liver injury through the KP-Kyn-AHR axis. This hypothesis will be tested with the following aims: 1) To determine the role of the AHR against cholestatic liver injury. 2) To demonstrate the role of the Trp-Kyn pathway and the molecular mechanism underlying its dysregulation in cholestatic liver disease. This study will clarify the critical role of AHR and KP in cholestatic liver injury. In outlines Kim, addition, this proposal an integrated training and research plan for the applicant receiving the mentorship from Drs. Kangho Cynthia Ju, and Kristin Eckel-Mahan,advisory committee members Drs. J. Marc Rhoad, Douglas G Burrin, Benny Abraham Kaipparettu, and Gao Xia. This training will ensure investigator resources objectives cholestatic liver K01 mitochondrial the applicant's transition to an independent in the liver pathology field with professional investigative skills. Furthermore, the outstanding provided by UTHealth and TMC will maximize the potential for the applicant to fulfill the career in identifying novel mechanisms underlying cholestasis and developing new therapeutics for liver disease. Given the longstanding interest and established ability of the applicant to study chronic disease, combined with excellent mentorship and the exceptional environment at UTHealth and TMC, this career development award will be pivotal in additional training n cholestasis, immune cell interaction, function, and therapeutic discovery, thereby facilitating a successful transition to independence. i
