Liver regeneration after acute injury, absent continuing harmful events, results in restoration of liver weight to body ratio (LBWR). This is achieved by a well-orchestrated series of proliferative events, in which all hepatic... [ view full abstract ]
Liver regeneration after acute injury, absent continuing harmful events, results in restoration of liver weight to body ratio (LBWR). This is achieved by a well-orchestrated series of proliferative events, in which all hepatic cells participate. Liver regeneration after partial hepatectomy in rodents has been the most often-used model to study this process. This procedure allows for surgical removal of intact hepatic lobes, uncomplicated from inflammatory events typically associated with tissue injury. Acute removal of hepatic tissue by 2/3 partial hepatectomy (PHx) is followed by a rapid activation of signals in the first 60 minutes. These include initiation of extracellular matrix remodeling and degradation, activation of receptor tyrosine kinases EGFR and MET in hepatocytes, release of HGF, TGFβ and norepinephrine the peripheral blood, and activation of Wnt and Hedgehog pathways. Later events include signaling by IL6, TNF and bile acids, serotonin, and leptin among others. Transcription factors such as beta catenin and Notch (NICD portion) are present in hepatocyte nuclei within 30 minutes after PHx, followed by mobilization and nuclear localization of STAT3, NFkB, FXR, etc. Cyclin D1 nuclear localization is considered as an irreversible commitment of hepatocytes to enter into DNA synthesis. Proliferating hepatocytes produce (and receive) paracrine signals which stimulate adjacent hepatic cells (stellate and endothelial cells) to enter into proliferation. Proliferation of endothelial cells and macrophages also involves migration of precursors from bone marrow. Cells in all lobular zones participate and regeneration proceeds as a gradient form periportal to centrilobular areas. Liver regeneration after PHx is carried out by participation of the existing mature hepatocytes of the adult liver. It is not mediated by precursor or progenitor cells, unless proliferation of hepatocytes is inhibited; typically, the latter involves increased expression of p21. In that setting, progenitor cells emerge from the biliary compartment and transdifferentiate into hepatocytes.
A multiplicity of signals are known to be involved in termination of liver regeneration. These include signaling of restored extracellular matrix via integrin linked kinase (ILK), enhanced expression of LSP1 and regulation of Yap expression. Undoubtedly there are more signals than these and the termination of liver regeneration is likely to be more complex than the initiation of the process. The final LBWR is adjusted to “status quo ante” as expected by the “hepatostat”, a term used to described the overall set of processes that determine LBWR under normal conditions.
While regeneration after acute injury has beneficial effects, chronic liver injury causing continual liver regeneration may have deleterious results. Chronic toxic conditions, including alcoholism, viral infections, NASH, etc., cause random death of hepatocytes, triggering proliferation of the residual surviving cells. Such proliferation occurs in a genotoxic environment of chronic inflammation, often associated with increased O2- radicals, lipid peroxides, etc. In such conditions of continual hepatocyte proliferation there is decrease in average hepatocyte ploidy and emergence of increased aneuploidy due to random loss of chromosomes. The latter is associated with allelic imbalance allowing “recessive” mutations to be expressed in diploid/aneuploid cells. Depending on the genes affected, this process may lead to cancer. Chronic hepatocyte loss uncompensated by hepatocyte proliferation is additionally associated with activation of stellate cells, resulting in increased deposition of extracellular matrix and triggering histologic changes that may lead to cirrhosis. It should also be noted that chronic inflammation associated with genetic diseases (e.g. hemochromatosis, alpha-1 antitrypsin deficiency, lipid and glycogen storage diseases) interferes with proliferation of hepatocytes, allowing only cells that randomly do not carry the genetic defect (“resistant” hepatocytes) to proliferate and maintain the “hepatostat”. This “oligoclonal” liver regeneration even further enhances the risk of formation of hepatocellular carcinoma (HCC). It is typical that in the above diseases, in most instances, the resulting HCC do not carry the genetic defect. Evidence will be presented that HCV may also operate through the same process and result in increased formation of HCC by inhibiting proliferation of infected hepatocytes via the Hippo pathway.
