RT Journal Article
SR Electronic
T1 Liver FoxO1 overexpression is positively associated with the degree of liver injury in cirrhotic patients
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.11.05.369504
DO 10.1101/2020.11.05.369504
A1 Esther Fernandez-Galán
A1 Silvia Sandalinas
A1 Blai Morales-Romero
A1 Laura Macias
A1 Montse Pauta
A1 Jordi Ribera
A1 Gregori Casals
A1 Loreto Boix
A1 Jordi Bruix
A1 Wladimiro Jimenez
A1 Manuel Morales-Ruiz
YR 2020
UL http://biorxiv.org/content/early/2020/11/05/2020.11.05.369504.abstract
AB Introduction Chronic liver disease is associated with high mortality. Liver transplantation is the definitive treatment for patients with end-stage liver disease, improving their survival and quality of life. However, chronic rejection of the graft and the imbalance between the demand and the availability of organs limit its applicability. Therefore, finding therapeutic and/or diagnostic alternatives for these patients is a priority. In this context, preclinical studies in rodents have demonstrated that Akt plays a key role in liver dysfunction. Even with all this evidence, the activation status of Akt and its downstream targets in the liver of patients with chronic hepatopathy is still unknown. Hence, the present study aims to determine the activation status of the molecules involved in the Akt signaling pathway in livers of cirrhotic patients.Materials and Methods In this study, 36 liver tissue samples from a cohort of 27 cirrhotic patients and 9 patients without cirrhosis were included. A total of 10 proteins involved in Akt/mTOR pathway (GSK3β, IGF1R, IRS1, mTOR, p70S6K, IR, PTEN, GSK3α, TSC2, and RPS6) were analyzed using a multiplex immunoassay based on Luminex® technology.Results Significant differences were found in several Akt/mTOR target proteins between the groups of cirrhotic patients vs. non-cirrhotic: FoxO1 (9.5 vs. 4.4; p<0.01), p-Akt (2.1 vs. 1.0; p<0.01), PTEN (3.061 vs. 1.877; p<0.05) and p70S6K (196.3 vs. 270.5; p<0.001). FoxO1 showed the best correlation with biochemical markers of liver injury aspartate aminotransferase and serum alanine aminotransferase (ASAT: r=0.51, p<0.05; ALAT: r=0.49, p<0.05). Moreover, the individual influence of FoxO1 on these parameters was confirmed by multiple regression analysis. It was the only enzyme in the Akt signaling pathway identified as a positive independent predictor of increased ASAT and ALAT levels.Conclusion FoxO1 is overexpressed in the liver of cirrhotic patients after partial hepatectomy. FoxO1 levels are also associated with the degree of liver injury, showing a positive correlation with current biomarkers used in clinical practice to detect liver injury.Competing Interest StatementThe authors have declared no competing interest.AktProtein kinase BHCCHepatocellular carcinomaeNOSEndothelial nitric oxide synthaseFoxO1Forkhead box protein O1GSK3αGlycogen synthase kinase 3 alphaGSK3βGlycogen synthase kinase 3 betaGRK2G protein-coupled receptor kinase 2IRInsulin receptorIRS1Insulin receptor substrate 1MFIMedian Fluorescence IntensitymTORMammalian target of rapamycin.PDK1Phosphoinositide-dependent protein kinase 1PI3-KPhosphoinositide 3-kinasePTENPhosphatidylinositol 3,4,5-trisphosphate 3-phosphataseRPS6Ribosomal protein S6TNFαTumor necrosis factor alphaTSC2Tuberous sclerosis complex 2p70S6KRibosomal protein S6 kinase beta-1DRUDensitometric relative units