Wilson disease (WD) is a metabolic disorder of copper (Cu) homeostasis that can present significant diagnostic and treatment challenges. Despite the well-established cause, the mechanisms behind WD pathologies remain only coarsely defined, hindering enhanced therapies’ development. At the Lutsenko lab in the Department of Physiology, we have identified specific molecular links connecting Cu overload to changes in the activity of liver X receptor (LXR) in the mouse model of WD. In Atp7b−/− mice with established liver disease and human WD, Cu overload activates the stress-sensitive transcription factor Nrf2. Nrf2 targets, especially sulfotransferase 1e1 (SULT1E1), are strongly induced and cause elevation of sulfated sterols, whereas oxysterols are decreased. This sterol misbalance results in the inhibition of the LXR and upregulation of LXR targets associated with inflammatory responses. Pharmacological inhibition of SULT1E1 partially reverses oxysterol misbalance and LXR inhibition. Contribution of this pathway to advanced hepatic WD was demonstrated by treating mice with an LXR agonist. We further showed that after the onset of metabolic changes, inflammation, and fibrosis in the WD liver, treatment with an LXR agonist can lessen these manifestations. Thus, our findings indicate that the identified pathway is an important driver of WD pathogenesis downstream of elevated Cu. Modulation of LXR activity should be investigated as a therapeutic approach to supplement chelation in WD.
Questions & Answers
Why did you choose Johns Hopkins for your work?
My interest in understanding the role of redox metals, especially copper and iron, in Wilson disease led me to join Johns Hopkins. Johns Hopkins is one of the best research universities in the world. In addition, the lab was a perfect fit for me and proved an excellent choice.
What does receiving this award mean to you personally and professionally? Do you have any connection with the particular award you received?
The award means a lot to me, and I hope it will help my career in the future. Having a master’s degree in biochemistry, I used to read and study the textbook Lehninger Principles of Biochemistry. I feel honored to receive an award named after the great biochemist Albert Lehninger.
What contributed to your project’s success?
The work environment in the lab is the main contributor to my project’s success. I continuously receive great support from my mentors (Professor Svetlana Lutsenko and Dr. James P. Hamilton) and colleagues, and I appreciate every one of them.
What thoughts do you have about Young Investigators’ Day itself, as a celebration of the roles student and fellows play in research at Johns Hopkins?
Motivation is one of the many things that keep us going and let us continue to strive for our dreams. Young Investigators’ Day sparks this motivation by recognizing and encouraging young researchers for their outstanding contributions to research excellence at Johns Hopkins. I am grateful to have been selected and will keep working untiringly to contribute to significant research advances in science.
What has been your best/most memorable experience while at Johns Hopkins?
I think it was when my paper was finally published after more than three years of work.
What are your plans over the next year or so?
I want to stay in academia. I am looking for a faculty position.
Tell me something interesting about yourself that makes you unique. Do you have any special hobbies, interests or life experiences?
I grew up in the mountains (Northwest Himalaya region) in India and was the first person with a doctorate in my village to pursue a career in medicine and science. In my free time, I love reading novels and traveling.