The capability of the liver to fully regenerate after injury is a unique phenomenon essential for the maintenance of its important functions in the control of metabolism and xenobiotic detoxification. The regeneration process is histologically well described, but the genes that orchestrate liver regeneration have been only partially characterized. Of particular interest are cytokines and growth factors, which control different phases of liver regeneration. Historically, their potential functions in this process were addressed by analyzing their expression in the regenerating liver of rodents. Some of the predicted roles were confirmed using functional studies, including systemic delivery of recombinant growth factors, neutralizing antibodies or siRNAs prior to liver injury or during liver regeneration. In particular, the availability of genetically modified mice and their use in liver regeneration studies has unraveled novel and often unexpected functions of growth factors, cytokines and their downstream signalling targets in liver regeneration. This review summarizes the results obtained by functional studies that have addressed the roles and mechanisms of action of growth factors and cytokines in liver regeneration after acute injury to this organ.
SummaryConcomitant hepatocyte apoptosis and regeneration is a hallmark of chronic liver diseases (CLDs) predisposing to hepatocellular carcinoma (HCC). Here, we mechanistically link caspase-8-dependent apoptosis to HCC development via proliferation- and replication-associated DNA damage. Proliferation-associated replication stress, DNA damage, and genetic instability are detectable in CLDs before any neoplastic changes occur. Accumulated levels of hepatocyte apoptosis determine and predict subsequent hepatocarcinogenesis. Proliferation-associated DNA damage is sensed by a complex comprising caspase-8, FADD, c-FLIP, and a kinase-dependent function of RIPK1. This platform requires a non-apoptotic function of caspase-8, but no caspase-3 or caspase-8 cleavage. It may represent a DNA damage-sensing mechanism in hepatocytes that can act via JNK and subsequent phosphorylation of the histone variant H2AX.
The liver has a unique regenerative capability, which involves extensive remodelling of cell-cell and cell-matrix contacts. Here we study the role of integrins in mouse liver regeneration using Cre/loxP-mediated gene deletion or intravenous delivery of b1-integrin siRNA formulated into nanoparticles that predominantly target hepatocytes. We show that although short-term loss of b1-integrin has no obvious consequences for normal livers, partial hepatectomy leads to severe liver necrosis and reduced hepatocyte proliferation. Mechanistically, loss of b1-integrin in hepatocytes impairs ligand-induced phosphorylation of the epidermal growth factor and hepatocyte growth factor receptors, thereby attenuating downstream receptor signalling in vitro and in vivo. These results identify a crucial role and novel mechanism of action of b1-integrins in liver regeneration and demonstrate that protein depletion by nanoparticle-based delivery of specific siRNA is a powerful strategy to study gene function in the regenerating liver.
The nuclear factor erythroid-derived 2, like 2 (Nrf2) transcription factor is a key regulator of the antioxidant defense system, and pharmacological activation of Nrf2 is a promising strategy for prevention of toxin-induced liver damage. However, the consequences of Nrf2 activation on liver regeneration (LR) have not been determined. To address this question, we generated mice expressing a constitutively active Nrf2 (caNrf2) mutant in hepatocytes. Expression of the transgene did not affect liver homeostasis. Surprisingly, however, there was no beneficial effect of Nrf2 activation on CCl 4 -induced liver injury and fibrosis. Most important, LR after partial hepatectomy was impaired in caNrf2-transgenic mice as a result of delayed hepatocyte proliferation and enhanced apoptosis of these cells after liver injury. Mechanistically, this involved up-regulation of the cyclin-dependent kinase inhibitor p15 and the proapoptotic protein Bcl2l11 (Bim). Using chromatin immunoprecipitation, we show that the p15 and Bcl2l11 genes are direct targets of Nrf2, which are activated under hyperproliferative conditions in the liver. Conclusion: Activated Nrf2 delays proliferation and induces apoptosis of hepatocytes in the regenerating liver. These negative effects of Nrf2 activation on LR should be considered when Nrf2-activating compounds are used for prevention of liver damage. (HEPATOLOGY 2014;60:670-678) See Editorial on Page 461 T he use of oxygen as an electron acceptor confronts aerobic organisms with the danger of reactive oxygen species (ROS) being formed as by-products of the respiratory chain. ROS formation can be further enhanced by nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, which are particularly abundant in inflammatory cells.1 Low levels of ROS are required for intracellular signaling, 2 but excessive levels damage all types of cellular macromolecules. To limit ROS-induced cell damage, aerobes developed strategies for efficient ROS detoxification. Of particular importance is the transcription factor nuclear factor erythroid-derived 2, like 2 (Nrf2), which controls expression of numerous genes encoding antioxidant proteins and ROS-detoxifying enzymes. 3Under homeostatic conditions, Nrf2 is retained in the cytoplasm by binding to Keap1, which also targets Nrf2 for proteasomal degradation. However, some Nrf2 molecules escape this inhibitory mechanism and translocate to the nucleus, where they bind to antioxidant response elements (AREs) in the promoter/ enhancer regions of their target genes. This leads to a basal expression of most Nrf2 target genes. In the
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