2024-03-29T15:43:57Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1762032022-12-20T14:03:34Zcom_10261_105com_10261_1com_10261_25col_10261_358col_10261_278
Engineered fibroblast growth factor 19 protects from acetaminophen-induced liver injury and stimulates aged liver regeneration in mice
Alvarez-Sola, Gloria
Uriarte, Iker
Latasa, Maria U.
Jimenez, Maddalen
Barcena-Varela, Marina
Santamaría, Eva
Urtasun, Raquel
Rodriguez-Ortigosa, Carlos
Prieto, Jesús
Corrales, Fernando J.
Baulies, Anna
García-Ruiz, Carmen
Fernández-Checa, José C.
Berraondo, Pedro
Fernández-Barrena, Maite G.
Berasain, Carmen
Ávila, Matías A.
Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España)
Instituto de Salud Carlos III
European Commission
Ministerio de Economía y Competitividad (España)
National Institute on Alcohol Abuse and Alcoholism (US)
Ministerio de Ciencia, Innovación y Universidades (España)
Fundación MTorres
Fundación Eugenio Rodríguez Pascual
Fundación Mario Losantos del Campo
Fundación Familia Puig-Infante
Fundación "la Caixa"
The liver displays a remarkable regenerative capacity triggered upon tissue injury or resection. However, liver regeneration can be
overwhelmed by excessive parenchymal destruction or diminished by pre-existing conditions hampering repair. Fibroblast growth
factor 19 (FGF19, rodent FGF15) is an enterokine that regulates liver bile acid and lipid metabolism, and stimulates hepatocellular
protein synthesis and proliferation. FGF19/15 is also important for liver regeneration after partial hepatectomy (PH). Therefore
recombinant FGF19 would be an ideal molecule to stimulate liver regeneration, but its applicability may be curtailed by its short
half-life. We developed a chimaeric molecule termed Fibapo in which FGF19 is covalently coupled to apolipoprotein A-I. Fibapo
retains FGF19 biological activities but has significantly increased half-life and hepatotropism. Here we evaluated the proregenerative activity of Fibapo in two clinically relevant models where liver regeneration may be impaired: acetaminophen (APAP)
poisoning, and PH in aged mice. The only approved therapy for APAP intoxication is N-acetylcysteine (NAC) and no drugs are
available to stimulate liver regeneration. We demonstrate that Fibapo reduced liver injury and boosted regeneration in APAPintoxicated mice. Fibapo improved survival of APAP-poisoned mice when given at later time points, when NAC is ineffective.
Mechanistically, Fibapo accelerated recovery of hepatic glutathione levels, potentiated cell growth-related pathways and increased
functional liver mass. When Fibapo was administered to old mice prior to PH, liver regeneration was markedly increased. The
exacerbated injury developing in these mice upon PH was attenuated, and the hepatic biosynthetic capacity was enhanced. Fibapo
reversed metabolic and molecular alterations that impede regeneration in aged livers. It reduced liver steatosis and downregulated
p21 and hepatocyte nuclear factor 4 α (Hnf4α) levels, whereas it stimulated Foxm1b gene expression. Together our findings
indicate that FGF19 variants retaining the metabolic and growth-promoting effects of this enterokine may be valuable for the
stimulation of liver regeneration.
2019-02-15T12:55:21Z
2019-02-15T12:55:21Z
2017-10-05
artículo
Cell Death and Disease 8: e3083 (2017)
http://hdl.handle.net/10261/176203
10.1038/cddis.2017.480
2041-4889
http://dx.doi.org/10.13039/100000027
http://dx.doi.org/10.13039/501100004587
http://dx.doi.org/10.13039/501100000780
http://dx.doi.org/10.13039/501100003329
http://dx.doi.org/10.13039/100008055
28981086
eng
Publisher's version
https://doi.org/10.1038/cddis.2017.480
Sí
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2015-66515-R
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2015-69944-R
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016-75972-R
http://creativecommons.org/licenses/by/4.0/
openAccess
Springer Nature