Removing a single gene engaged in embryonic liver development eliminated the bile ducts in newborn mice, researchers found in a study recently published in Cell Reports. Despite this significant flaw in their bile excretion system, the small and yellow-colored mice survived for up to 8 months and were physically active.

The data suggest why certain patients with cholestasis seem to perform better than others with seemingly matching genetic compositions. Researchers believe the answer lies in the unique cell-signaling pathway activated to adjust to liver injury. This path has never been investigated from the perspective of adaptation before.

“Our finding was quite serendipitous,” admits senior author Satdarshan Paul Monga, MD, professor at the University of Pittsburgh’s Department of Medicine, Pennsylvania. “We discovered that mice with a deletion of an embryonic gene YAP1 [yes-associated protein 1] in the early precursors of liver cells don’t form bile ducts at all. But surprisingly, those animals didn’t die—rather, their livers figured out a way to shunt the excess bile into the bloodstream instead of poisoning themselves.”


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The scientists observed a phenotype that resembles human Alagille syndrome in mice deficient in the YAP1 gene. In the absence of bile ducts, instead of being poisoned by bile, the liver of those mice adapted to the injury by producing less bile and deflecting it to the bloodstream instead of emptying it into the liver, making it less poisonous.

This new intrinsic adaptive mechanism might explain why some patients with liver damage develop symptoms of severe liver toxicity later than others. It might also provide signs to clinicians about new methods of treating those patients. 

“The severity of symptoms in patients with genetic defects in the liver varies dramatically,” said first author Laura Molina, PhD, medical student at the University of Pittsburgh. “Our research suggests that YAP1 could be an elusive disease modifier that regulates disease outcomes in these patients. We hope that, by studying the functions of YAP1 and promoting the mechanism of adaptation, we can better understand the liver disease and improve existing treatments.”

References

Missing bile ducts offer clues to mechanism of liver injury. News Release. University of Pittsburgh, Schools of the Health Sciences; July 6, 2021 

Molina LM, Zhu J, Li Q, et al. Compensatory hepatic adaptation accompanies permanent absence of intrahepatic biliary network due to YAP1 loss in liver progenitors. Cell Rep. 2021;36(1):109310. doi:10.1016/j.celrep.2021.109310