Bile acids are cholesterol metabolites that are well known for their role in fat digestion. Many liver diseases such as gallstones, fatty liver disease, congenital disorders lead to cholestasis, which is characterized as accumulation of bile acids in the liver. The Anakk laboratory at the University of Illinois investigated how the function and metabolic abilities of the liver are hampered during different disease states using transcriptomic approaches.
In a new article published in JHEP Reports, a group of researchers led by Sayeepriyadarshini “Sayee” Anakk, faculty member in the Department of Molecular and Integrative Physiology, studied fatty liver disease, hepatitis, NASH (Non-Alcoholic Steato Hepatitis), cholestasis, and liver regeneration. The liver is primarily responsible for the breakdown and removal of foreign compounds, including prescription drugs. One would anticipate that diseased livers will have impaired functions and struggle to detoxify compounds. As expected, genome-wide sequencing revealed that the liver function was compromised in most of the liver disorders. However, in cholestasis, researchers uncovered that some of the detoxification genes were induced.
“We noted that higher anesthetic concentration was needed to sedate the cholestatic mice,” which jumpstarted this project, Anakk said. Constitutive androstane receptor (CAR) transcriptionally regulates all the metabolic gene programs that help degrade the foreign compounds and clear them from the system.
“I was really surprised to find CAR activation only in cholestatic livers, not in the patients suffering from Hepatitis B or C infections, nor in fatty liver diseases,” added Bhoomika Mathur, PhD graduate from the Anakk lab who is now a postdoctoral researcher at the University of Texas Southwestern Medical Center. Perhaps one can speculate that the sick cholestatic liver enhances its detoxification machinery as a final resort, they said.
One way to test this was to challenge cholestatic mice with acetaminophen (Tylenol). Tylenol at very high concentrations is toxic to the liver. Control animals showed severe liver injury within six hours, whereas the cholestatic livers were protected against this injury. This protection was significantly reduced when CAR activity was inhibited, highlighting the importance of CAR in safeguarding the diseased liver.
To examine the clinical relevance of their findings, the Anakk lab examined the livers of biliary atresia patients in collaboration with Dr. Sanjiv Harpavat at the Texas Children’s Hospital. Biliary atresia is a genetic condition, and these patients develop cholestasis and ultimately require liver transplants to survive beyond childhood. Researchers found that one of the CAR downstream target protein, CYP2B6, was expressed in higher amounts in biliary atresia compared to normal liver tissue.
“This data supports some of the unexplained increases in drug clearance noted in cholestatic individuals in the 1970s,” Anakk added. A recent study of biliary atresia patients found that a subset of patients with a longer survival had elevated glutathione activity. As CAR can also contribute towards glutathione levels, the Anakk laboratory investigated the glutathione concentrations after the Tylenol challenge and found that the cholestatic mice were able to replenish glutathione concentrations quickly.
Anakk and Mathur said they hope that the clinicians managing cholestatic patients will begin testing for detoxification pathways in the tissue biopsies. If CAR targets are induced, the physicians could tailor the treatment and investigate if this gives them a survival advantage. On the contrary, it is also relevant to ponder whether these individuals need a higher dose of medicine as their metabolism may clear it faster. Therefore, balancing a fine line between the therapeutic goals and the observed increases in drug metabolism is one of the implications of this study.
Their article, “Transcriptomic analysis across liver diseases reveals disease-modulating activation of constitutive androstane receptor in cholestasis,” elaborates their research and conclusions. In addition to the Anakk laboratory, the collaboration included the laboratories of Kristina Schoonjan from École Polytechnique Fédérale de Lausanne in Switzerland, Auinash Kalsotra at the University of Illinois Urbana-Champaign, Antony Wheatley at the National University of Ireland, and Dr. Harpavat at Texas Children’s Hospital.
The National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health and American Cancer Society supported this research.