Mapping early serum proteome signatures of liver regeneration in living donor liver transplant cases

Abstract

The liver is the only solid organ capable of regenerating itself to regain 100% of its mass and function after liver injury and/or partial hepatectomy (PH). This exceptional property represents a therapeutic opportunity for severe liver disease patients. However, liver regeneration (LR) might fail due to poorly understood causes. Here, we have investigated the regulation of liver proteome and phosphoproteome at a short time after PH (9 h), to depict a detailed mechanistic background of the early LR phase. Furthermore, we analyzed the dynamic changes of the serum proteome and metabolome of healthy living donor liver transplant (LDLT) donors at different time points after surgery. The molecular profiles from both analyses were then correlated. Insulin and FXR‐FGF15/19 signaling were stimulated in mouse liver after PH, leading to the activation of the main intermediary kinases (AKT and ERK). Besides, inhibition of the hippo pathway led to an increased expression of its target genes and of one of its intermediary proteins (14‐3‐3 protein), contributing to cell proliferation. In association with these processes, metabolic reprogramming coupled to enhanced mitochondrial activity cope for the energy and biosynthetic requirements of LR. In human serum of LDLT donors, we identified 56 proteins and 13 metabolites statistically differential which recapitulate some of the main cellular processes orchestrating LR in its early phase. These results provide mechanisms and protein mediators of LR that might prove useful for the follow‐up of the regenerative process in the liver after PH as well as preventing the occurrence of complications associated with liver resection.

Molecular basis of Progressive Familial Intrahepatic Cholestasis 3. A proteomics study

“…In the present study we described a general down-regulation of OCM enzymes in PFIC3 livers, which might facilitate cell proliferation for tissue injury repair while the maintenance of MAT2A and B levels support the regulated nature of the process, in contrast to the uncontrolled cell growth that is typically found in cancer development. It is tempting to speculate that the systematic monitoring of OCM would be a useful tool to assess the physiological status of the liver and to allow for discrimination among a controlled regenerative process and tumor progression 45 . It has been also reported that some OCM metabolites might provide alternative therapeutic options.…”

Discrimination of Etiologically Different Cholestasis by Modeling Proteomics Datasets

“…This multisubunit transmembrane complex is part of the mitochondrial electron transport chain, which drives oxidative phosphorylation. Altered mitochondrial functions have been observed in chronic liver diseases, including alcohol-induced liver disease, nonalcoholic fatty liver disease, viral hepatitis, liver regeneration [28], and primary and secondary cholestasis. Major changes included impairment of the electron transport chain and/or oxidative phosphorylation, leading to decreased oxidative metabolism of various substrates and decreased ATP synthesis [29].…”