Scientists from the University of California-Davis have discovered an important difference between mice and humans regarding: how human livers heal. The difference centers on a protein called PPARα, which activates liver regeneration. Normally, mouse PPARα is far more active and efficient than the human form, allowing mice to quickly regenerate damaged livers. However, the research shows that protein fibroblast growth factor 21 (FGF21) can boost the regenerative effects of human PPARα.
The team’s study (“Forced expression of fibroblast growth factor 21 reverses the sustained impairment of liver regeneration in hPPARαPAC mice due to dysregulated bile acid synthesis”), published in Oncotarget, suggests that the molecule could offer significant therapeutic benefits for patients who have had a liver transplant or suffer from liver disease.
“Compared to mouse PPARα, human PPARα has a reduced capacity to regulate metabolic pathways required for liver regeneration,” wrote the investigators. “In addition, FGF21 can compensate for the reduced ability of human PPARα in stimulating liver regeneration, which suggests the potential application of FGF21 in promoting hepatic growth in injured and steatotic livers in humans.”
“We found that FGF21 is a good rescuing molecule that facilitates liver regeneration and perhaps tissue repair,” said Yu-Jui Yvonne Wan, Ph.D., vice chair for research in the department of pathology and laboratory medicine at UC Davis and senior author on the paper. “Our data suggests that FGF21 could help with liver regeneration, either after removal or after damage caused by alcohol or a virus.”
In the study, human and mouse PPARα showed different capacities for liver regeneration after surgery. Even after having two-thirds of their livers removed, normal mice regained their original liver mass within seven to 10 days. By contrast, mice with human PPARα never fully regenerated, even after three months.
However, by increasing FGF21, the team boosted human PPARα's ability to regenerate and heal mouse livers.
While mouse PPARα has regenerative advantages over the human version, there is also a downside, as this ability can lead to cancer. Human PPARα does not cause cancer; however, as noted, it cannot match the mouse protein's regenerative capacity. This trade-off provides a number of advantages on the human side. For example, several popular drugs target PPARα to treat high cholesterol and triglycerides.
Still, in the right context, a more active human PPARα could be a great boon for patients with liver conditions. Using FGF21 to boost this regenerative capacity is an important step in that direction.