Liver FoxO1 overexpression is positively associated with the degree of liver injury in cirrhotic patients

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 Statement The authors have declared no competing interest. * Akt : Protein kinase B HCC : Hepatocellular carcinoma eNOS : Endothelial nitric oxide synthase FoxO1 : Forkhead box protein O1 GSK3α : Glycogen synthase kinase 3 alpha GSK3β : Glycogen synthase kinase 3 beta GRK2 : G protein-coupled receptor kinase 2 IR : Insulin receptor IRS1 : Insulin receptor substrate 1 MFI : Median Fluorescence Intensity mTOR : Mammalian target of rapamycin. PDK1 : Phosphoinositide-dependent protein kinase 1 PI3-K : Phosphoinositide 3-kinase PTEN : Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase RPS6 : Ribosomal protein S6 TNFα : Tumor necrosis factor alpha TSC2 : Tuberous sclerosis complex 2 p70S6K : Ribosomal protein S6 kinase beta-1 DRU : Densitometric relative units