Increased FGF21 May Spur Greater Liver Regeneration

Fibroblast growth factor 21 (FGF21) has been the focus of some interest in the research community in recent years. Raised levels of FGF21 have been shown to notably increase mean life span in mice, most likely primarily by interfering in mechanisms related to growth hormone. After more than a decade of earnest research into the mechanisms of aging and longevity in mammals, the longest lived mice are still those in which growth hormone or its receptor are disrupted, a comparatively early discovery in the field. There are numerous ways to influence these biochemical pathways, and altering levels of FGF21 is one of them.

Some researchers classify manipulation of FGF21 as a calorie restriction mimetic treatment given that mice engineered to have more FGF21 show some of the same changes as produced by the practice of calorie restriction. In the other direction, calorie restriction increases circulating FGF21 levels. Restricting only dietary methionine intake also seems to increase FGF21 levels at the same time as it extends healthy life spans in mice. However, other studies have shown that FGF21 isn't required for the production of these benefits. It is probably best to think of any area of metabolism as a machine with many interconnected levers and dials. You can achieve similar results by changing different settings, but not all of the options or the machinery are required for any given outcome, and it is far from straightforward to determine what is actually happening under the hood.

Here researchers find another interesting role for FGF21, picking up on differences in the efficiency of liver regeneration when comparing mice and humans. The first results are a little indirect, but further research should confirm whether or not the observed outcome will hold up in a medically useful context.

FGF21 boosts regenerative ability in mice carrying human PPARα protein

Researchers have illuminated an important distinction between mice and humans: 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 findings suggest that the molecule could offer significant therapeutic benefits for patients who have had a liver transplant or suffer from liver disease. "We found that FGF21 is a good rescuing molecule that facilitates liver regeneration and perhaps tissue repair. Our data suggests that FGF21 could help with liver regeneration, either after removal or after damage caused by alcohol or a virus."

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.

Forced expression of fibroblast growth factor 21 reverses the sustained impairment of liver regeneration in hPPARαPAC mice due to dysregulated bile acid synthesis

The current study demonstrated that PPARα-humanized mice (hPPARαPAC) mice exhibit reduced hepatocyte proliferative capability during liver regeneration in comparison with WT mice. The presented data showed that human PPARα-mediated signaling that controls liver regeneration was less effective than that of mouse PPARα. Thus, in response to liver regeneration, hPPARα is not as effective as mouse PPARα in regulating lipid metabolism as well as hepatocyte proliferation. Metabolism, which is mainly controlled by the liver, is about 7 times faster in mice than humans. Liver regeneration, which can be completed within 7-10 days in mice, takes about 60-90 days to complete in humans. Thus, it seems that the metabolic rate and proliferative capability are correlated, and that the species difference of PPARα may account for such difference.

Because overexpression of FGF21 could restore the normal progression of liver regeneration in hPPARαPAC mice, FGF21 appears to not only repair injury, but also compensate for the reduced ability of human PPARα to hasten liver regeneration. These findings suggest that FGF21 infusion would be of therapeutic value to improve the outcome of liver transplantation and liver disease in humans.


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