Abstract
The liver is characterized by unique regenerative properties to restore its mass and function after a partial loss. Hepatic regeneration arises after resection or following acute and chronic injuries. Resection and acute liver damage normally induce a regenerative process characterized by phenotypic fidelity, in which each cell type promotes its own replication and replacement. This process fails in chronic liver damage, where trans-differentiation of parenchymal cells or activation of facultative progenitors occurs. Both liver resection and acute/chronic damages alter redox homeostasis, as a consequence of blood flow changes, hypoxia, metabolism modification, and activation of inflammatory response. Even though formerly described as ‘oxidative stress’, altered redox homeostasis leads to the fine regulation of several pathways involved in liver regeneration, including the proliferation of parenchymal cells, trans-differentiation, and activation of facultative progenitors.
Several redox-dependent transcription factors and pathways implicated in the regenerative process of the liver were described, but pre-clinical experiments using different antioxidants were not fully conclusive. Even though accurate study designs to define appropriate dosages, treatment duration, and routes of administration are required, modulation of redox-dependent molecular pathways to enhance liver regeneration is even more intriguing. Preliminary studies focused on the identification of these targets will pave the way for viable therapies to be tested in clinical trials.
Introduction
The liver is an extraordinary organ dedicated to the preservation of whole-body homeostasis. Liver parenchyma is composed mainly of hepatocytes and cholangiocytes, two epithelial cell types that differentiate from common progenitors named hepatoblasts. Hepatocytes control energy metabolism, biosynthesis of molecules, and clearance of endogenous and exogenous toxic compounds, while cholangiocytes structure the biliary system (Rui 2014, Stanger 2015). Hepatocytes and cholangiocytes are also referred as parenchymal liver cells, constituting ~80% of liver mass; the remaining ~20% is composed of nonparenchymal liver cells, which include mainly hepatic stellate cells (HSCs), Kupffer cells (KCs), and liver sinusoidal endothelial cells (LSECs) (Forbes 2014).
The liver is provided with a special regenerative capacity (Fig. 1). Even though the liver is normally characterized by a low cell turnover, it is able to re-establish its original mass and function after damage (Michalopoulos 2007). This process is a very hot topic for both basic and clinical sciences, being accurately regulated and occurring in a very short time after resection of a definite mass amount, not only in animal models (partial hepatectomy (PHx)) but also in humans (partial liver transplantation (PLTx)) (Fausto et al. 2006, 2012). Hepatic resection or acute toxic injury are followed by the activation of regenerative activities characterized by phenotypic fidelity that is, replication of every cell through local cell proliferation (Michalopoulos 2007). Nevertheless, a failure of endogenous proliferation, which occurs mostly during persistent hepatic injury, stimulates alternative regenerative pathways, including activation of liver progenitors and/or trans-differentiation of parenchymal liver cells (Michalopoulos & Bhushan 2021).
The liver may regenerate through several mechanisms. (A) Hepatic resection activates a process characterized by phenotypic fidelity, that is, replication of every cell through local proliferation. (B) Chronic hepatic injury triggers alternative regenerative processes, trans-differentiation of parenchymal liver cells (upper panel), or differentiation of progenitors toward adult parenchymal cells from a regenerative niche (lower panel).
Citation: Redox Experimental Medicine 2022, 1; 10.1530/REM-22-0008
Damages inducing liver regeneration often induce alterations in redox balance, which may exert an impact on the regenerative process after injury (Kamata et al. 2005, Schwabe & Brenner 2006). Although the signaling pathways involved in both the ‘canonical’ and the alternative regenerative pattern are not completely characterized, several of them may be redox-dependent and may be of interest for both redox biology and redox medicine.
This review aims to summarize the redox-dependent mechanisms which may be involved in hepatic regeneration. Description of basic details of redox biology is beyond the scope of this review since several outstanding papers on this topic are available (Serviddio et al. 2013, Sies 2015, Flohe 2020, Sies 2020). After a concise presentation of the redox reactions and balance occurring in the liver, we will represent the recent knowledge of the role played by reactive species and redox signaling in the modulation of hepatic regenerative homeostasis, pointing out the most important clinical perspectives.
The hepatic redox homeostasis
The liver accounts for the metabolism of carbohydrates, lipids, and ammonia, biotransformation of endogenous and exogenous toxic compounds, and bile synthesis. The hepatic parenchyma is specialized through metabolic zonation associated with oxygen supply, to let different metabolic pathways proficiently operate in parallel, and to reduce futile cycles (Jungermann & Kietzmann 1996). It is worth to note that proliferating hepatocytes are mostly equidistant from the central and the portal vein (i.e. midlobular), while periportal and pericentral hepatocytes are not proliferating (Minocha et al 2017). Gene expression patterns and enzyme distribution in zonation are dynamic and regulated by not only nutrients, hormones but also oxygen and reactive species (Kietzmann 2017). Metabolic reactions in liver cells are modulated by the following:
-
subcellular organelles – most oxidative reactions take place in mitochondria and peroxisomes, while reductive reactions occur in the cytosol (Hinzpeter et al. 2017);
-
coenzyme availability – the couple oxidized/reduced NAD (NAD+/NADH) in catabolic (oxidative) reactions, and the couple oxidized/reduced NAD phosphate (NADP+/NADPH) in anabolic (reductive) reactions (Xiao et al. 2018);
-
cellular AMP/ATP ratio – increased ATP utilization and/or decreased ATP production promote catabolism via AMP‐activated protein kinase (AMPK); on the contrary, high ATP availability inhibits AMPK and switches metabolism toward anabolism (Foretz & Viollet 2011).
Origin of reactive species in the liver
In this review, the term ‘reactive species’ will refer to both reactive oxygen and nitrogen species. In the liver, reactive species are produced by several metabolic reactions which take place in different cell types and subcellular compartments.
In the cytosol of hepatocytes, xanthine oxidoreductase (XOR) is involved in the last two steps of purine catabolism, leading to the oxidation of hypoxanthine to xanthine, which is in turn oxidized to uric acid (Battelli et al. 2016). XOR mostly acts as a dehydrogenase in the human liver, transferring electrons to NAD+; nevertheless, XOR can be converted to an oxidase isoform by several stimuli, transferring electrons to O2 with the production of reactive species (Stirpe et al. 2002).
Through the respiratory chain complexes, hepatocellular mitochondria transfer electrons to NAD+, flavin mononucleotide, and flavin adenine dinucleotide (FAD), which act as carriers to reduce O2 in a multistep process linked with the production of reactive species (Zorov et al. 2014). Liver mitochondria normally produce 13–15% of hepatic H2O2 by consuming nearly 2% of O2 (Boveris et al. 1972, Zorov et al. 2014). Complexes I and III are the most important mitochondrial sources of reactive species, even though Complex II has also been described as a facultative producer (Moreno-Sanchez et al. 2013, Quinlan et al. 2013). Other mitochondrial sources of reactive species include monoamine oxidases A/B (Pizzinat et al. 1999) and cytochrome b5 reductase (Nishino & Ito 1986) in the outer membrane, α-glycerophosphate dehydrogenase (Mracek et al. 2009), dihydroorotate dehydrogenase (Forman & Kennedy 1975), the electron transfer flavoprotein ubiquinone oxidoreductase (Watmough & Frerman 2010), proline dehydrogenase and the branched-chain α-ketoacid dehydrogenase complex (Oldford et al. 2019) in the inner membrane, and α-ketoglutarate dehydrogenase and pyruvate dehydrogenase in the matrix (Oldford et al. 2019).
Peroxisomes are organelles involved not only in fatty acid catabolism, metabolism of pentose phosphates and D-amino acids but also in alternative alcohol oxidation and NAD+ regeneration through malate dehydrogenase and/or lactate dehydrogenase (Gronemeyer et al. 2013). XOR and the inducible isoform of nitrate synthase are also situated in peroxisomes (Angermuller et al. 1987, Tikhanovich et al. 2013). In the liver, peroxisomes account for about 20% of O2 consumption and 35% of H2O2 production, generating more reactive species than mitochondria (Fransen et al. 2012). H2O2 can promptly diffuse through the peroxisomal membrane by a porin-like channel or released in the cytoplasm by crystalloid core tubules (Fritz et al. 2007, Rokka et al. 2009).
The endoplasmic reticulum (ER) achieves crucial tasks in hepatocytes, including protein synthesis, trafficking and folding, calcium storage, and lipid, steroid, and xenobiotic metabolism (Liu & Green 2019). To oxidize sulfhydryl groups, protein folding needs a high oxidized (GSSG) to reduced (GSH) glutathione ratio in the ER lumen (Chakravarthi & Bulleid 2004). The protein disulphide isomerase (PDI) and ER oxidoreductin 1 (ERO1) are involved in the electron transport for protein folding: PDI directly accepts electrons, while ERO1 transfers electrons to O2 as final the acceptor, producing ~25% reactive species in hepatocytes (Malhotra & Kaufman 2007, Csala et al. 2010). The microsomal monooxygenase system, which includes fatty acid desaturase, squalene monooxygenase, and 7-dehydrocholesterol reductase (involved in lipid and steroid metabolism), is one of the most important sources of reactive species in the ER. Xenobiotic metabolism involves phase I monooxygenation reactions (by cytochromes P450 and the flavoprotein NADPH-cytochrome P450 reductase) and phase II conjugation reactions. The electron transfer from NADPH to P450 in the monooxygenation reaction shows a leakage that promotes the production of reactive species (Zeeshan et al. 2016). An additional leakage in the electron transfer process which causes the production of reactive species may occur via the NADH-cytochrome b5 reductase in fatty acid desaturation (Samhan-Arias & Gutierrez-Merino 2014).
Lysosomes are vital for autophagy, a particularly preserved recycling mechanism consisting of the removal of cellular elements. These organelles maintain hepatocellular energy balance by modulating metabolic enzymes, mitochondria quality, and substrate availability (Madrigal-Matute & Cuervo 2016). Lysosomes are protective against an excess of reactive species by removing injured mitochondria, unfolded proteins, and toxic cellular compounds (Rabinowitz & White 2010, Pohl & Dikic 2019). Lysosomes include an electron transport chain comprising ubiquinone, reduced by cytosolic NADH with O2 as the final electron acceptor; acidification of the lysosomal matrix induces the partial reduction of O2, generating reactive species (Gille & Nohl 2000, Nohl & Gille 2002).
Hepatic NADPH oxidase and NO synthases (NOS) are additional sources of reactive species. NADPH oxidase is located in both parenchymal and nonparenchymal liver cells (De Minicis et al. 2006). KCs present with a phagocytic form of NADPH oxidase, able to produce high amounts of reactive species (Katsuyama 2010). HSCs are provided with a non-phagocytic NADPH oxidase isoform, able to produce mild quantities of reactive species (Bataller et al. 2003, Adachi et al. 2005, Zhan et al. 2006). Hepatic NO synthases are constitutive (eNOS) in LSECs, and inducible (iNOS) in hepatocytes, KCs, HSCs, and LSECs. Production of NO by eNOS is determinant to maintain the hepatic blood flow (Diesen & Kuo 2010). The role of iNOS in the liver is very complex since it can be regulated by several cytokines leading to the formation of reactive species with both protective and harmful effects (Taylor et al. 1998, Diesen & Kuo 2010).
Antioxidants in the liver
The liver disposes of several antioxidants to neutralize the excessive production of reactive species and to preserve redox balance. Hepatic endogenous antioxidants may be classified asn enzymatic and non-enzymatic. Endogenous antioxidants work as a complex network of redox reactions between the cytosol and subcellular compartments.
Enzymatic antioxidants include superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), thioredoxin reductase (TRXR), glutathione peroxidase (GPX), and peroxiredoxin (PRX). SOD isoforms include Cu/Zn (SOD1 and SOD3) or Mn (SOD2) in their active site and account for the dismutation of superoxide anion (Fukai & Ushio-Fukai 2011). Cu/Zn-SOD is mostly located in the cytosol and lysosomes, while Mn-SOD is mostly sited in mitochondria (Okado-Matsumoto & Fridovich 2001). Among human tissues, the liver expresses the highest quantity of both CuZn-SOD and Mn-SOD (Marklund 1980). CAT is an iron-dependent peroxidase which transforms two H2O2 into two H2O and one O2. CAT activity in the human body is highest in the liver and erythrocytes (Goyal & Basak 2010). The hepatic GR, cytosolic and mitochondrial TRXRs (TRXR1 and TRXR2, respectively) use NADPH to reduce disulfides to dithiols. In the reaction catalyzed by GR, the dithiol reduces GSSG; as selenoproteins, TRXRs form selenothiol pairs which reduce TRX (Miller & Schmidt 2019). GPX isoforms are selenium-dependent peroxidases which are oxidized by the conversion of H2O2 into H2O or organic hydroperoxide (ROOH) to corresponding alcohol (ROH) and are reduced again by GSH. Eight GPX isoforms are reported in humans, but only GPX1, GPX2, GPX4 (phospholipid hydroperoxidase), and GPX7 are located in the liver (Toppo et al. 2008). GPX1, GPX2, and GPX7 target H2O2 in the cytosol, mitochondria (GPX1), extracellular space (GPX2 and GPX7), and endoplasmic reticulum (GPX7), while GPX4 targets ROOH in the cytosol, mitochondria, and nucleus (Toppo et al. 2008). The six isoforms of PRX (thiol hydrolases) can be oxidized by H2O2 or ROOH, being reduced again by TRX. The human liver expresses all PRX isoforms, targeting both H2O2 and ROOH in the cytosol (PRX1, PRX2, PRX5, and PRX6), mitochondria (PRX3 and PRX5), extracellular space (PRX4), nucleus (PRX5), and endosomes (PRX3 and PRX6) (Rhee et al. 2018).
Non-enzymatic antioxidants include GSH, thioredoxin (TRX), and ubiquinone (UQ). GSH, the most concentrated hepatocellular antioxidant, is a tripeptide with a sulfhydryl group in a cysteine residue, which exerts its reductant activity on several oxidized enzymes and antioxidants (Kretzschmar 1996). TRX is a tetrapeptide with two sulfhydryl groups in two cysteine residues exposed to reversible redox reactions by the NADPH‐dependent thioredoxin reductase. The reduced form of TRX is necessary to reduce oxidized peroxiredoxin, playing a determinant role in the hepatic redox homeostasis (Okuyama et al. 2008). UQ (or coenzyme Q) is contained in all liver cell types and, as lipophilic, is sited within several cell membranes, acting as an antioxidant in its reduced form (ubiquinol, UQH2). However, it can be partially reduced (ubisemiquinone, UQ•-), and the property to go through three different redox states allows it to act as an electron carrier from complexes I and II to complex III in the mitochondrial respiratory chain (Wang & Hekimi 2016). UQ is mostly concentrated in the Golgi vesicles, followed by mitochondria and lysosomes (Kalen et al. 1987).
Hepatic regeneration
The liver is provided with exceptional features of regeneration triggered by resection as well as different injuries (metabolic, viral, toxic, genetic, or immunologic). Both liver resection and acute/chronic injuries followed by organ regeneration are characterized by perturbations in redox homeostasis. In a healthy liver, functional cells replace the loss of liver mass according to the phenotypic fidelity (Michalopoulos 2013). Nevertheless, a continual or acute liver injury may impair the replicative capacity of mature liver cells, triggering alternative pathways of regeneration. One of these pathways includes the activation and differentiation of hepatic progenitor cells (HPCs, also termed oval cells in rodents) via ductular reaction (Espanol-Suner et al. 2012). Another pathway is characterized by trans-differentiation of hepatic parenchymal cells, that is, hepatocytes and cholangiocytes act as facultative stem cells for each other (Michalopoulos & Khan 2015).
Regeneration induced by hepatic resection
Liver parenchymal cells are mitotically quiescent (G0 state), but a loss of liver mass induces quick proliferation of hepatocytes. Current understanding of liver regeneration derives from PHx in rodents, which consists of surgical removal of 70% liver mass, or toxin-induced hepatic injury. Liver regeneration following PHx classically recognizes three phases (immediate/early events, proliferation, and termination; Fig. 2), regulated by orchestrated molecular and cellular pathways which induce activation of nonparenchymal cells and proliferation of the remnant adult parenchymal cells (Michalopoulos & Bhushan 2021).
Regeneration following hepatic resection can be schematized in three subsequent stages: (1) immediate/early events include (i) increased hepatic portal flow, with consequent shear stress and hypoxia, leading to the release of vascular endothelial growth factor (VEGF) and nitric oxide (NO), (ii) remodeling of the extracellular matrix followed by the release of hepatocyte growth factor (HGF) and epithelial growth factor (EGF), (iii) acute inflammation which triggers secretion of interleukin-6 (IL-6) and tumor necrosis factor (TNF); (2) proliferation, characterized by the transition of mitotically quiescent (G0 state) toward cycling (G1 state) cells; (3) termination, in during which the integrin-linked kinase (ILK) promotes differentiation and stops proliferation of hepatocytes.
Citation: Redox Experimental Medicine 2022, 1; 10.1530/REM-22-0008
Increase in portal venous flow is the first event in the hepatic regenerative process, causing hemodynamic changes, which include enlarged sinusoidal diameter, increased fenestration, and widening of the intercellular spaces (Morsiani et al. 1998). These changes promote shear stress on LSECs, which in turn release NO-inducing cell proliferation and angiogenesis through vascular endothelial growth factor (VEGF) (Carnovale & Ronco 2012). Furthermore, portal venous flow holds several signaling factors from extrahepatic organs, such as EGF, insulin, glucagon, and bile acids (Michalopoulos & Bhushan 2021). Finally, increased portal venous flow may cause hepatic hypoxia, with consequent activation of the hypoxia-inducible factors (HIFs), additional promoters of liver regeneration (Maeno et al. 2005).
An early event following PHx is the activation of a urokinase-type plasminogen activator, which in turn activates metalloproteinases and leads to the breakdown and remodeling of extracellular matrix (ECM) (Kim et al. 1997). This results in the activation and release of hepatocyte growth factor (HGF) that, in association with EGF and other signaling molecules, promotes the Ras/Raf/MEK/ERK and the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)–protein kinase B (PKB)–mammalian target of rapamycin (mTOR) pathways, with the transition from G1 to S and from G2 to M phase in proliferating parenchymal cells (Lindroos et al. 1991, Fausto et al. 2006). The next early event is represented by acute inflammation, with increased levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor (TNF) and downstream activation of Janus Kinase (JAK)/Signal Transducer and Activator of Transcription 3 (STAT3) pathway, with the transition from G0 to G1 in quiescent hepatocytes (Cressman et al. 1995, Blindenbacher et al. 2003).
Proliferation of both parenchymal and nonparenchymal liver cells is regulated by a series of intracellular and extracellular events, controlled by signaling pathways classified according to their effect on hepatic regeneration: (i) complete mitogens, whose ablation stops the process; (ii) auxiliary/partial mitogens, which support the regenerative response, even though their ablation does not abolish it; (iii) complex mediators, which include multiple elements not completely characterized (Michalopoulos & Bhushan 2021). Complete mitogens include HGF and its receptor c-MET, EGF, amphiregulin, tumor growth factor-α (TGF-α), and heparin-αbinding EGF-like growth factor (HB-EGF) as ligands of the EGF receptor (Michalopoulos 2007, Michalopoulos 2013). Several pathways are recognized as auxiliary/partial mitogen signals, including the already cited TNF and IL-6, VEGF and its receptors, bile acids and farnesoid-X-receptor, noradrenalin and its α1 receptor, and different hormones such as insulin, leptin, serotonin, and growth hormone (Cressman et al. 1996, Yamada et al. 1998, Han et al. 2008, Fafalios et al. 2011, Borude et al. 2012). Complex mitogenic signals include the Wnt-β-catenin system, the Hedgehog and the Hippo-YAP pathways, and the TGF-β1 signaling (Yang et al. 2014, Swiderska-Syn et al. 2016, Patel et al. 2017, Oh et al. 2018). In particular, TGF-β1 signaling is a complex pathway controlling the hepatocyte cell cycle and response to mitogens: TGF-β1 inhibits mitosis so that its removal from the liver after PHx is associated with cell proliferation, while its subsequent rise is concomitant to termination of regeneration (Michalopoulos & Bhushan 2021).
Cessation of liver regeneration is characterized by the gradual acquisition of a quiescent phenotype of parenchymal cells, accompanied by the renewal of ECM, a process regulated by a network of signals between hepatocytes and HSCs (Rudolph et al. 1999). In this network, a determinant role is played by the integrin-linked kinase (ILK), which induces differentiation and stops the proliferation of hepatocytes (Gkretsi et al. 2008).
Alternative mechanisms of liver regeneration
Severe or chronic hepatic damage may induce hepatocellular senescence, causing a disruption in the regenerative mechanisms of liver parenchymal cells (Marshall et al. 2005).
In the setting of biliary injury, hepatocytes may exhibit phenotypic plasticity and trans-differentiate toward biliary-like cells to fix a cholestatic damage (Nejak-Bowen 2020). Although several mediators may be involved in this process, YAP activation plays an essential role (Pepe-Mooney et al. 2019). More than supplying a pool of cells to help recover injured bile ducts in severe biliary disease, hepatocytes may acquire transient biliary-like functionality (Gadd et al. 2020).
Severe hepatocellular injury may induce direct conversion of cholangiocytes to hepatocytes (Deng et al. 2018). Nevertheless, it is possible that less severe injury might also trigger de-differentiation of cholangiocytes to a bipotent progenitor state, through the so-called ‘ductular reaction’ (Sell 1998). The intrahepatic bile ductules (or canals of Hering, located between hepatocytes and the bile ducts) represent the anatomical site of hepatic regenerative niches, in which HPCs expressing both hepatocyte and cholangiocyte markers emerge and proliferate in response to severe or chronic liver injury (Xiao et al. 2003, Miyajima et al. 2014). HPC activation is accompanied by ECM remodeling, macrophage infiltration, and myofibroblast stimulation, involving several signaling pathways mediated by Wnt/β-catenin, Notch, and TNF-related weak inducer of apoptosis (TWEAK) (Jakubowski et al. 2005, Boulter et al. 2012). Moreover, YAP and mammalian target of rapamycin complex 1 (mTORC1) signals have been recently reported as determinants for HPC activation, since these pathways positively modulate the growth of cholangiocyte-derived organoids and the proliferation of HPCs in mice (Planas-Paz et al. 2019). Proliferation of HPCs is further regulated by several inflammation-related cytokines (TNF, IL-6) and growth factors (HGF/MET, VEGF, and TGF-β) (So et al. 2020). The origin of HPCs was defined by lineage tracing studies, which described cholangiocytes as sources of HPCs in several models (Schaub et al. 2014, Tarlow et al. 2014a, Raven et al. 2017). However, different lineage tracing investigations in chronic liver injury models reported hepatocytes as a supplementary source of HPCs through metaplastic process (Yanger et al. 2013, Tarlow et al. 2014b, Yanger & Stanger 2014). Mechanisms supporting hepatocyte metaplasia involve both YAP and Notch signaling (Yanger et al. 2013, Yimlamai et al. 2014, Pepe-Mooney et al. 2019). It is worth to note that HPC-dependent hepatic regeneration is not effective in repairing the loss of liver mass in severe or chronic liver diseases (Weng et al. 2015). Furthermore, the persistence of undifferentiated HPCs amplifies inflammation and fibrosis (Lukacs-Kornek & Lammert 2017). On the contrary, stimulating HPC differentiation may simultaneously lead to functional parenchymal cells and mitigation of fibrosis.
Redox control of hepatic regeneration
Although formerly considered harmful, reactive species are progressively involved in several cell fate outcomes and signalling pathways (Holmstrom & Finkel 2014). In the liver, oxidants modulate several processes that may impact hepatic regeneration. We will elucidate redox-dependent mechanisms implicated in liver regeneration occurring after PHx/PLTx or in severe or chronic liver diseases (Table 1).
Redox-dependent modulators of hepatic regeneration.
| Type and phase of regeneration | Regulatory factor | Role | References | |
|---|---|---|---|---|
| Regeneration following liver resection | Immediate/early phase | Nitric oxide | Vasodilation | Carnovale et al. (2000) |
| Induction of DNA synthesis | ||||
| HIF-1α | Hepatocellular metabolism | Maeno et al. (2005) | ||
| Angiogenesis | Tajima et al. (2009) | |||
| HIF-2α | Angiogenesis | Kron et al. (2016) | ||
| Proliferation | H2O2 | Induction of HB-EGF and amphiregulin | Miyazaki et al. (1996) | |
| NF-κB | Induction of TNF and IL-6 | Mullen et al. (2020) | ||
| NRF2 | Induction of IL-6 | Wruck et al. (2011) | ||
| Activation of insulin/IGF-1R | Beyer et al. (2008) | |||
| Nucleoredoxin | Inhibition of Wnt/β-catenin | Funato et al. (2006) | ||
| FOXOs | Inhibition of cell cycle | Essers et al. (2005) | ||
| HIF-1α | Activation of Hedgehog | Bijlsma et al. (2008) | ||
| TRX1 | MST1 inhibition | Chae et al. (2012) | ||
| YAP activation | Wang et al. (2019) | |||
| Termination | O2- | ILK inhibition | Saito et al. (2004) | |
| NO | ILK impairment | Reventun et al. (2017) | ||
| Alternative pathways of liver regeneration | NRF2 | p21 signaling | Fan et al. (2014) | |
| Activation and differentiation of HPCs | Bellanti et al. (2021) | |||
FOXOs, forkhead box O transcription factors; HB-EGF, heparin-binding EGF-like growth factor; HIFs, hypoxia inducible factors; HPCs, hepatic progenitor cells; IGF-1R, insulin-like growth factor-1 receptor; IL-6, interleukin-6; ILK, integrin-linked kinase; MST1, mammalian sterile 20-like kinase-1; NF-κB, nuclear factor-κB; NRF2, nuclear factor erythroid 2-related factor 2, TNF, tumor necrosis factor; TRX1, thioredoxin-1; YAP, yes associated protein.
Redox involvement in regeneration after hepatic resection
Hepatic resection induced by PHx or PLTx is characterized by an excess of reactive species, which were mainly ascribed to intermittent inflow occlusion (Guerrieri et al. 1999, Senoner et al. 2019). It is conceivable that molecular pathways regulated by reactive species would be determinant in the process of regeneration following hepatic resection. On the other side, antioxidant treatments demonstrated to improve liver regeneration, suggesting that high concentrations of reactive species might be harmful in this process (Zeng et al. 2015, Cordoba-Jover et al. 2019). Thus, current evidence indicates that redox homeostasis is a determinant for the outcome of hepatic regeneration.
Modification of redox status in immediate/early events
Liver resection induces significant perfusion changes in the organ remnant, which influence hepatic functions via immediate modifications in O2 supply, followed by indirect alterations of cellular metabolism. Indeed, since hepatic arterial and venous blood flow and pressure compensate for each other, increase in portal pressure is balanced by contraction of the hepatic artery (hepatic arterial buffer response) (Eipel et al. 2010). This means that the liver remnant receives a high portal and a low arterial blood flow, with reduced O2 tension (Smyrniotis et al. 2002).
NO is a short-lived and highly unstable reactive species acting as both intra- and extracellular signaling molecule to modulate vasodilation and angiogenesis (Cooke & Losordo 2002). Hepatic NO concentration and metabolism are increased immediately after resection, associated with liver-specific cytokine-dependent overexpression of iNOS (Hortelano et al. 1995). More than regulating vascular dynamics in regenerating liver, NO is involved in the induction of DNA synthesis, even though it can partially promote lipid peroxidation (Carnovale et al. 2000). It is worth to note that NO is not the only redox-related mediator for hepatic vasodilation after resection since an upregulation of heme-oxygenase 1 (HO-1) by KCs promotes the production of carbon monoxide to contribute to vasodilation (Eipel et al. 2010).
Blood flow changes after liver resection cause local hypoxia with consequent activation of the redox-dependent transcription factors HIFs. HIF-1α is able to regulate hepatocellular metabolism and angiogenesis during liver regeneration induced by PHx (Maeno et al. 2005, Tajima et al. 2009). HIF-2α is also activated by resection-induced hypoxia, to coordinate the proliferation of hepatocytes with VEGF-driven LSECs reconstruction and angiogenesis (Kron et al. 2016). This redox-sensitive mechanism can be pharmacologically modulated to accelerate the process of liver regeneration, as suggested by studies using prolactin-induced HIF-1α-VEGF axis or prolyl hydrolase inhibitors (Olazabal et al. 2009, Schadde et al. 2017). Furthermore, blood flow changes induced by PHx alter the remodeling of sinusoids affecting shear stress-induced eNOS, accounting for senescent LSECs via Notch activation, but Sirtuin 1 inhibition was able to promote liver regeneration by abolishing Notch-induced senescence (Duan et al. 2022). The latter is the first study demonstrating that LSEC senescence is triggered by endothelial Notch activation, with Sirtuin 1 as a direct target of Notch (Duan et al. 2022).
Redox modulation of proliferation pathways
Redox balance is involved in the regulation of several growth factors implicated in the proliferation of hepatocytes. HGF and its receptor c-MET, main regulators of hepatocellular proliferation, are also key modulators of the cellular redox state in a multimodal manner, but particularly upregulating the antioxidant GSH system, and repressing NADPH oxidase and CYP2E1 (Clavijo-Cornejo et al. 2013). In gastric mucosal cells, hydrogen peroxide is able to induce the expression of HB-EGF and amphiregulin in a concentration-dependent manner, and this induction is blocked by co-treatment with the antioxidant N-acetylcysteine (Miyazaki et al. 1996). In rat liver cells, hydrogen peroxide induces phosphorylation of EGF receptor, promoting transformation (Huang et al. 2001).
Cytokine-associated pathways involved in regeneration after hepatic resection are greatly influenced by the redox state. Mild concentrations of reactive species activate the transcription factor nuclear factor-κB, a potent inducer of TNF, IL-1β, IL-6, and its downstream STAT3 molecule expression (Mullen et al. 2020). Of interest, the IL-6 promoter matches an antioxidant response element and is strongly activated by the nuclear factor erythroid 2-related factor 2 (NRF2), one of the most important redox-sensitive transcription factors (Wruck et al. 2011). TGF-β inhibits hepatocyte proliferation, while its inactivation leads to increased proliferative response after liver resection (Russell et al. 1988, Romero-Gallo et al. 2005). The family of NADPH oxidases is recognized targets of TGF-β, mediating many of its effects on several liver cells and influencing liver regeneration after resection (Herranz-Iturbide et al. 2021).
Hormones involved in liver regeneration after PHx/PLTx may be modulated by cellular and extracellular redox state, including norepinephrine, growth hormone, insulin, and thyroid hormone, all of which in turn induce the Ras/Raf/MEK/ERK and PI3K/PKB/mTOR signaling pathways (Abu Rmilah et al. 2020). Of note, the contribution of insulin/insulin growth factor-1 receptor signaling in liver regeneration after PHx requires NRF2, since its inactivation leads to oxidative stress-related insulin resistance, impairing the activation of anti-apoptotic and pro-mitogenic pathways (Beyer et al. 2008). Of interest, NRF2 is dynamically regulated following PHx, showing activation in the presence of a pro-oxidant agent (such as ethanol) or antioxidant compounds, suggesting that this pathway may be triggered by liver resection independently of redox status (Morales-González et al. 2017).
Redox homeostasis alterations affect all the complex mitogenic signals involved in liver regeneration after PHx/PLTx. Overexpression of nucleoredoxin, a TRX family protein, selectively inhibits the Wnt/β-catenin pathway, while its ablation accelerates cell proliferation through Ras or MEK (Funato et al. 2006). Low amounts of reactive species promote the interaction between β-catenin and forkhead box O (FOXO) transcription factors, inhibiting the cell cycle progression (Essers et al. 2005). On the other side, Wnt/β-catenin signaling is necessary for hepatocyte protection against reactive species-mediated apoptosis, inducing the phosphorylation of FOXO3 and increasing hepatocyte proliferation (Tao et al. 2013). The Hedgehog cascade may be triggered by HIF-1α through hypoxia consequent to hepatic resection (Bijlsma et al. 2008). It is also worth to note that Hedgehog is a target of Wnt/β-catenin in the liver, suggesting a redox-dependent crosstalk between these pathways in regeneration following hepatic resection (Gebhardt 2014). The Hippo-YAP pathway is variably modulated by redox homeostasis, producing different functional outcomes. YAP, the main downstream effector of the Hippo cascade, is inactivated by the mammalian Ste20-like kinases 1/2 (MST1/2). Interestingly, TRX1 may prevent MST1 activation, while reactive species trigger MST1 activity, with opposite effects on YAP (Chae et al. 2012, Wang et al. 2019). Furthermore, the redox state may directly regulate YAP expression and activity in the liver (Wu et al. 2013).
Redox commitment in termination of regeneration
ILK is a key determinant for termination of liver regeneration after Phx, since its ablation causes enhanced proliferation of parenchymal cells and hepatomegaly, associated with Hippo-YAP activation (Apte et al. 2009). A model of transient focal cerebral ischemia showed that superoxide inhibits ILK, while SOD expression is associated with increased ILK level (Saito et al. 2004). In damaged vascular endothelium, ILK protein stability and signaling cascade were impaired by high amounts of NO produced by iNOS (Reventun et al. 2017). These studies support the hypothesis that ILK is repressed by reactive species (including NO) in the early and intermediate phase of liver regeneration; when termination is approaching, redox balance tunes toward a reduced status, allowing ILK signaling to coordinate termination of regeneration.
Redox-dependent modulation of alternative liver regeneration pathways
The mechanisms underlying liver parenchymal cell trans-differentiation or ductular reaction involve key regulators of transcription (such as YAP, Wnt/β-catenin, Notch, TWEAK, and mTORC1), cytokines (TNF and IL-6), and growth factors (HGF/c-MET and VEGF). As already described, all these pathways are redox-responsive and take place following liver resection. Nevertheless, redox modifications are not triggered by blood flow modifications with reduced O2 tension and shear stress. On the contrary, the impairment of redox homeostasis characterizing acute and chronic liver conditions contributes to disease pathogenesis, accounting for dysfunction or death of parenchymal cells (Medina & Moreno-Otero 2005, Mari et al. 2010). Hepatocellular trans-differentiation and ductular reaction are associated with metabolic changes, which include downregulation of oxidative pathways and mitochondrial dysfunction (Serviddio et al. 2013, Caldez et al. 2018).
When hepatocyte proliferation is impaired by loss of β1-integrin or p21 overexpression, cholangiocytes may behave as facultative progenitors to contribute to hepatocellular regeneration (Raven et al. 2017). Evidence from a model of toxic liver injury suggests that p21 signaling follows oxidative burst and is coordinated with the NRF2 pathway, expression of antioxidant genes, and control of the oxidative injury (Fan et al. 2014). Hepatic damage induced by thioacetamide (TAA) or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) is followed by regeneration sustained by biliary epithelial cells (Deng et al. 2018). Of note, liver damage induced by both TAA and DDC administration is associated with alterations of redox homeostasis which induce upregulation of the NRF2 cascade (Stankova et al. 2010, Demirel et al. 2012, Singla et al. 2012). These data indicate that the master antioxidant regulator NRF2 could play a determinant role in the trans-differentiation process of liver parenchymal cells, but further specific investigations need to address this hypothesis.
Persistent hepatic chronic damage leads to an excess in reactive species with consequent oxidative stress, which may induce a senescent phenotype of parenchymal cells, impairing their capacity to proliferate (Roskams 2006, Bellanti & Vendemiale 2021). Thus, the ductular reaction occurs as a response to an oxidative injury, leading to HPC activation in a specialized microenvironment defined as a regenerative niche (Michelotti et al. 2016, Govaere et al. 2019, Overi et al. 2020). Nevertheless, the contribution of HPC activation and differentiation from hepatic niches is questioned, because of a lower efficiency with respect to phenotypic fidelity and trans-differentiation (Michalopoulos & Bhushan 2021). The final fate of HPC differentiation process is determined by different signaling pathways occurring in the niche, which is dependent on the etiology of liver injury (Boulter et al. 2012, Govaere et al. 2019). Regenerative niches are sites of multifaceted immunological events played by both immune and non-immune cells, and redox signaling is determinant in the fine tuning of the immune response in the HPC niche (Bellanti et al. 2020). More than modulating the immune signals within and around the niche, recent evidence demonstrates that the redox-dependent transcription factor NRF2 is a key determinant of HPC fate since its inhibition triggers their activation and differentiation (Bellanti et al. 2021). Further research is needed to clarify whether other redox-dependent transcription factors may potentially regulate the commitment of undifferentiated progenitors toward specific hepatic lineages.
Concluding remarks
Changes in redox homeostasis occur both following hepatic resection and during acute or chronic liver injuries. Understanding of several redox-dependent transcription factors and pathways implicated in the regenerative process of the liver has significantly improved in the last years. Several studies tested the hypothesis that antioxidants would boost liver regeneration by counteracting the negative effects of reactive species. Pre-clinical experiments using silymarin, quercetin, curcumin, resveratrol, baicalein, geraniol, and melatonin showed controversial results, suggesting the need for accurate study designs to define appropriate dosages, treatment duration, and routes of administration (Canbek & Yaylaci 2018). Furthermore, pharmacological modulation of redox-dependent molecular pathways to enhance liver regeneration represents a fascinating aim of the research. Indeed, pioneering reports suggest that potent pharmacologic activation of NRF2 is a potential approach to improve hepatic regeneration (Dayoub et al. 2013, Chan et al. 2021). Pre-clinical studies aimed at the definition of these targets will identify viable therapies to be tested in human trials.
Declaration of interest
The authors have no competing interests to declare. Francesco Bellanti is an Editor of Redox Experimental Medicine. Francesco Bellanti was not involved in the review or editorial process for this paper, on which he is listed as an author.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
Author contribution statement
F B wrote the first draft of the manuscript. G V and G S wrote sections of the manuscript and substantially contributed to the conception of the new version of the work. All authors contributed to manuscript revision, read, and approved the submitted version.
References
Abu Rmilah AA, Zhou W & Nyberg SL 2020 Hormonal contribution to liver regeneration. Mayo Clinic Proceedings: Innovations, Quality and Outcomes 4 315–338. (https://doi.org/10.1016/j.mayocpiqo.2020.02.001)
Adachi T, Togashi H, Suzuki A, Kasai S, Ito J, Sugahara K & Kawata S 2005 NAD(P)H oxidase plays a crucial role in PDGF-induced proliferation of hepatic stellate cells. Hepatology 41 1272–1281. (https://doi.org/10.1002/hep.20719)
Angermuller S, Bruder G, Volkl A, Wesch H & Fahimi HD 1987 Localization of xanthine oxidase in crystalline cores of peroxisomes. A cytochemical and biochemical study. European Journal of Cell Biology 45 137–144.
Apte U, Gkretsi V, Bowen WC, Mars WM, Luo JH, Donthamsetty S, Orr A, Monga SP, Wu C & Michalopoulos GK 2009 Enhanced liver regeneration following changes induced by hepatocyte-specific genetic ablation of integrin-linked kinase. Hepatology 50 844–851. (https://doi.org/10.1002/hep.23059)
Bataller R, Schwabe RF, Choi YH, Yang L, Paik YH, Lindquist J, Qian T, Schoonhoven R, Hagedorn CH, Lemasters JJ, et al.2003 NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis. Journal of Clinical Investigation 112 1383–1394. (https://doi.org/10.1172/JCI18212)
Battelli MG, Polito L, Bortolotti M & Bolognesi A 2016 Xanthine oxidoreductase-derived reactive species: physiological and pathological effects. Oxidative Medicine and Cellular Longevity 2016 3527579. (https://doi.org/10.1155/2016/3527579)
Bellanti F, Pannone G, Tartaglia N & Serviddio G 2020 Redox control of the immune response in the hepatic progenitor cell niche. Frontiers in Cell and Developmental Biology 8 295. (https://doi.org/10.3389/fcell.2020.00295)
Bellanti F & Vendemiale G 2021 The aging liver: redox biology and liver regeneration. Antioxidants and Redox Signaling 35 832–847. (https://doi.org/10.1089/ars.2021.0048)
Bellanti F, di Bello G, Iannelli G, Pannone G, Pedicillo MC, Boulter L, Lu WY, Tamborra R, Villani R, Vendemiale G, et al.2021 Inhibition of nuclear factor (erythroid-derived 2)-like 2 promotes hepatic progenitor cell activation and differentiation. npj Regenerative Medicine 6 28. (https://doi.org/10.1038/s41536-021-00137-z)
Beyer TA, Xu W, Teupser D, Ulrich auf dem K, Bugnon P, Hildt E, Thiery J, Kan YM & Werner S 2008 Impaired liver regeneration in Nrf2 knockout mice: role of ROS-mediated insulin/IGF-1 resistance. EMBO J 27 212–223. (https://doi.org/10.1038/sj.emboj.7601950)
Bijlsma MF, Leenders PJ, Janssen BJ, Peppelenbosch MP, Ten CH & Spek CA 2008 Endogenous hedgehog expression contributes to myocardial ischemia-reperfusion-induced injury. Experimental Biology and Medicine 233 989–996.(https://doi:)
Blindenbacher A, Wang X, Langer I, Savino R, Terracciano L & Heim MH 2003 Interleukin 6 is important for survival after partial hepatectomy in mice. Hepatology 38 674–682. (https://doi.org/10.1053/jhep.2003.50378)
Borude P, Edwards G, Walesky C, Li F, Ma X, Kong B, Guo GL & Apte U 2012 Hepatocyte-specific deletion of farnesoid X receptor delays but does not inhibit liver regeneration after partial hepatectomy in mice. Hepatology 56 2344–2352. (https://doi.org/10.1002/hep.25918)
Boulter L, Govaere O, Bird TG, Radulescu S, Ramachandran P, Pellicoro A, Ridgway RA, Seo SS, Spee B, Van Rooijen N, et al.2012 Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nature Medicine 18 572–579. (https://doi.org/10.1038/nm.2667)
Boveris A, Oshino N & Chance B 1972 The cellular production of hydrogen peroxide. Biochemical Journal 128 617–630. (https://doi.org/10.1042/bj1280617)
Caldez MJ, Van Hul N, Koh HWL, Teo XQ, Fan JJ, Tan PY, Dewhurst MR, Too PG, Talib SZA, Chiang BE, et al.2018 Metabolic remodeling during liver regeneration. Developmental Cell 47 425 .e5–438.e5. (https://doi.org/10.1016/j.devcel.2018.09.020)
Canbek M & Yaylaci AO 2018 The effects of antioxidants on liver regeneration. Biomedical Journal of Scientific and Technical Research 6 5368–5370. (https://doi.org/10.26717/BJSTR.2018.06.001375)
Carnovale CE, Scapini C, Alvarez ML, Favre C, Monti J & Carrillo MC 2000 Nitric oxide release and enhancement of lipid peroxidation in regenerating rat liver. Journal of Hepatology 32 798–804. (https://doi.org/10.1016/s0168-8278(0080249-4)
Carnovale CE & Ronco MT 2012 Role of nitric oxide in liver regeneration. Annals of Hepatology 11 636–647. (https://doi.org/10.1016/S1665-2681(1931436-X)
Chae JS, Gil Hwang S, Lim DS & Choi EJ 2012 Thioredoxin-1 functions as a molecular switch regulating the oxidative stress-induced activation of MST1. Free Radical Biology and Medicine 53 2335–2343. (https://doi.org/10.1016/j.freeradbiomed.2012.10.527)
Chakravarthi S & Bulleid NJ 2004 Glutathione is required to regulate the formation of native disulfide bonds within proteins entering the secretory pathway. Journal of Biological Chemistry 279 39872–39879. (https://doi.org/10.1074/jbc.M406912200)
Chan BKY, Elmasry M, Forootan SS, Russomanno G, Bunday TM, Zhang F, Brillant N, Starkey Lewis PJ, Aird R, Ricci E, et al.2021 Pharmacological activation of Nrf2 enhances functional liver regeneration. Hepatology 74 973–986. (https://doi.org/10.1002/hep.31859)
Clavijo-Cornejo D, Enriquez-Cortina C, Lopez-Reyes A, Dominguez-Perez M, Nuno N, Dominguez-Meraz M, Bucio L, Souza V, Factor VM, Thorgeirsson SS, et al.2013 Biphasic regulation of the NADPH oxidase by HGF/c-Met signaling pathway in primary mouse hepatocytes. Biochimie 95 1177–1184. (https://doi.org/10.1016/j.biochi.2013.01.005)
Cooke JP & Losordo DW 2002 Nitric oxide and angiogenesis. Circulation 105 2133–2135. (https://doi.org/10.1161/01.cir.0000014928.45119.73)
Cordoba-Jover B, Arce-Cerezo A, Ribera J, Pauta M, Oro D, Casals G, Fernandez-Varo G, Casals E, Puntes V, Jimenez W, et al.2019 Cerium oxide nanoparticles improve liver regeneration after acetaminophen-induced liver injury and partial hepatectomy in rats. Journal of Nanobiotechnology 17 112. (https://doi.org/10.1186/s12951-019-0544-5)
Cressman DE, Diamond RH & Taub R 1995 Rapid activation of the Stat3 transcription complex in liver regeneration. Hepatology 21 1443–1449. (https://doi.org/10.1002/hep.1840210531)
Cressman DE, Greenbaum LE, DeAngelis RA, Ciliberto G, Furth EE, Poli V & Taub R 1996 Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science 274 1379–1383. (https://doi.org/10.1126/science.274.5291.1379)
Csala M, Margittai E & Banhegyi G 2010 Redox control of endoplasmic reticulum function. Antioxidants and Redox Signaling 13 77–108. (https://doi.org/10.1089/ars.2009.2529)
Dayoub R, Vogel A, Schuett J, Lupke M, Spieker SM, Kettern N, Hildt E, Melter M & Weiss TS 2013 Nrf2 activates augmenter of liver regeneration (ALR) via antioxidant response element and links oxidative stress to liver regeneration. Molecular Medicine 19 237–244. (https://doi.org/10.2119/molmed.2013.00027)
De Minicis S, Bataller R & Brenner DA 2006 NADPH oxidase in the liver: defensive, offensive, or fibrogenic? Gastroenterology 131 272–275. (https://doi.org/10.1053/j.gastro.2006.05.048)
Demirel U, Yalniz M, Aygun C, Orhan C, Tuzcu M, Sahin K, Ozercan IH & Bahcecioglu IH 2012 Allopurinol ameliorates thioacetamide-induced acute liver failure by regulating cellular redox-sensitive transcription factors in rats. Inflammation 35 1549–1557. (https://doi.org/10.1007/s10753-012-9470-5)
Deng X, Zhang X, Li W, Feng RX, Li L, Yi GR, Zhang XN, Yin C, Yu HY, Zhang JP, et al.2018 Chronic liver injury induces conversion of biliary epithelial cells into hepatocytes. Cell Stem Cell 23 114 .e3–122.e3. (https://doi.org/10.1016/j.stem.2018.05.022)
Diesen DL & Kuo PC 2010 Nitric oxide and redox regulation in the liver: Part I. General considerations and redox biology in hepatitis. Journal of Surgical Research 162 95–109. (https://doi.org/10.1016/j.jss.2009.09.019)
Duan JL, Ruan B, Song P, Fang ZQ, Yue ZS, Liu JJ, Dou GR, Han H & Wang L 2022 Shear stress-induced cellular senescence blunts liver regeneration through Notch-sirtuin 1-P21/P16 axis. Hepatology 75 584–599. (https://doi.org/10.1002/hep.32209)
Eipel C, Abshagen K & Vollmar B 2010 Regulation of hepatic blood flow: the hepatic arterial buffer response revisited. World Journal of Gastroenterology 16 6046–6057. (https://doi.org/10.3748/wjg.v16.i48.6046)
Espanol-Suner R, Carpentier R, Van Hul N, Legry V, Achouri Y, Cordi S, Jacquemin P, Lemaigre F & Leclercq IA 2012 Liver progenitor cells yield functional hepatocytes in response to chronic liver injury in mice. Gastroenterology 143 1564 .e7–1575.e7. (https://doi.org/10.1053/j.gastro.2012.08.024)
Essers MA, de Vries-Smits LM, Barker N, Polderman PE, Burgering BM & Korswagen HC 2005 Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science 308 1181–1184. (https://doi.org/10.1126/science.1109083)
Fafalios A, Ma J, Tan X, Stoops J, Luo J, Defrances MC & Zarnegar R 2011 A hepatocyte growth factor receptor (Met)-insulin receptor hybrid governs hepatic glucose metabolism. Nature Medicine 17 1577–1584. (https://doi.org/10.1038/nm.2531)
Fan X, Chen P, Tan H, Zeng H, Jiang Y, Wang Y, Wang Y, Hou X, Bi H & Huang M 2014 Dynamic and coordinated regulation of KEAP1-NRF2-ARE and p53/p21 signaling pathways is associated with acetaminophen injury responsive liver regeneration. Drug Metabolism and Disposition: The Biological Fate of Chemicals 42 1532–1539. (https://doi.org/10.1124/dmd.114.059394)
Fausto N, Campbell JS & Riehle KJ 2006 Liver regeneration. Hepatology 43 (Supplement 1) S45–S53. (https://doi.org/10.1002/hep.20969)
Fausto N, Campbell JS & Riehle KJ 2012 Liver regeneration. Journal of Hepatology 57 692–694. (https://doi.org/10.1016/j.jhep.2012.04.016)
Flohe L 2020 Looking back at the early stages of redox biology. Antioxidants 9 1254. (https://doi.org/10.3390/antiox9121254)
Forbes SJ 2014 Recent advances in stem cells and regenerative medicine. QJM 107 251–252. (https://doi.org/10.1093/qjmed/hcu032)
Foretz M & Viollet B 2011 Regulation of hepatic metabolism by AMPK. Journal of Hepatology 54 827–829. (https://doi.org/10.1016/j.jhep.2010.09.014)
Forman HJ & Kennedy J 1975 Superoxide production and electron transport in mitochondrial oxidation of dihydroorotic acid. Journal of Biological Chemistry 250 4322–4326. (https://doi.org/10.1016/S0021-9258(1941421-X)
Fransen M, Nordgren M, Wang B & Apanasets O 2012 Role of peroxisomes in ROS/RNS-metabolism: implications for human disease. Biochimica et Biophysica Acta 1822 1363–1373. (https://doi.org/10.1016/j.bbadis.2011.12.001)
Fritz R, Bol J, Hebling U, Angermuller S, Volkl A, Fahimi HD & Mueller S 2007 Compartment-dependent management of H(2)O(2) by peroxisomes. Free Radical Biology and Medicine 42 1119–1129. (https://doi.org/10.1016/j.freeradbiomed.2007.01.014)
Fukai T & Ushio-Fukai M 2011 Superoxide dismutases: role in redox signaling, vascular function, and diseases. Antioxidants and Redox Signaling 15 1583–1606. (https://doi.org/10.1089/ars.2011.3999)
Funato Y, Michiue T, Asashima M & Miki H 2006 The thioredoxin-related redox-regulating protein nucleoredoxin inhibits Wnt-beta-catenin signalling through dishevelled. Nature Cell Biology 8 501–508. (https://doi.org/10.1038/ncb1405)
Gadd VL, Aleksieva N & Forbes SJ 2020 Epithelial plasticity during liver injury and regeneration. Cell Stem Cell 27 557–573. (https://doi.org/10.1016/j.stem.2020.08.016)
Gebhardt R 2014 Speeding up hepatocyte proliferation: how triiodothyronine and beta-catenin join forces. Hepatology 59 2074–2076. (https://doi.org/10.1002/hep.26984)
Gille L & Nohl H 2000 The existence of a lysosomal redox chain and the role of ubiquinone. Archives of Biochemistry and Biophysics 375 347–354. (https://doi.org/10.1006/abbi.1999.1649)
Gkretsi V, Apte U, Mars WM, Bowen WC, Luo JH, Yang Y, Yu YP, Orr A, St-Arnaud R, Dedhar S, et al.2008 Liver-specific ablation of integrin-linked kinase in mice results in abnormal histology, enhanced cell proliferation, and hepatomegaly. Hepatology 48 1932–1941. (https://doi.org/10.1002/hep.22537)
Govaere O, Cockell S, Van Haele M, Wouters J, Van Delm W, Van den Eynde K, Bianchi A, van Eijsden R, Van Steenbergen W, Monbaliu D, et al.2019 High-throughput sequencing identifies aetiology-dependent differences in ductular reaction in human chronic liver disease. Journal of Pathology 248 66–76. (https://doi.org/10.1002/path.5228)
Goyal MM & Basak A 2010 Human catalase: looking for complete identity. Protein and Cell 1 888–897. (https://doi.org/10.1007/s13238-010-0113-z)
Gronemeyer T, Wiese S, Ofman R, Bunse C, Pawlas M, Hayen H, Eisenacher M, Stephan C, Meyer HE, Waterham HR, et al.2013 The proteome of human liver peroxisomes: identification of five new peroxisomal constituents by a label-free quantitative proteomics survey. PLoS ONE 8 e57395. (https://doi.org/10.1371/journal.pone.0057395)
Guerrieri F, Vendemiale G, Grattagliano I, Cocco T, Pellecchia G & Altomare E 1999 Mitochondrial oxidative alterations following partial hepatectomy. Free Radical Biology and Medicine 26 34–41. (https://doi.org/10.1016/s0891-5849(9800145-2)
Han C, Bowen WC, Michalopoulos GK & Wu T 2008 Alpha-1 adrenergic receptor transactivates signal transducer and activator of transcription-3 (Stat3) through activation of Src and epidermal growth factor receptor (EGFR) in hepatocytes. Journal of Cellular Physiology 216 486–497. (https://doi.org/10.1002/jcp.21420)
Herranz-Iturbide M, Lopez-Luque J, Gonzalez-Sanchez E, Caballero-Diaz D, Crosas-Molist E, Martin-Mur B, Gut M, Esteve-Codina A, Jaquet V, Jiang JX, et al.2021 NADPH oxidase 4 (Nox4) deletion accelerates liver regeneration in mice. Redox Biology 40 101841. (https://doi.org/10.1016/j.redox.2020.101841)
Hinzpeter F, Gerland U & Tostevin F 2017 Optimal compartmentalization strategies for metabolic microcompartments. Biophysical Journal 112 767–779. (https://doi.org/10.1016/j.bpj.2016.11.3194)
Holmstrom KM & Finkel T 2014 Cellular mechanisms and physiological consequences of redox-dependent signalling. Nature Reviews: Molecular Cell Biology 15 411–421. (https://doi.org/10.1038/nrm3801)
Hortelano S, Dewez B, Genaro AM, Diaz-Guerra MJ & Bosca L 1995 Nitric oxide is released in regenerating liver after partial hepatectomy. Hepatology 21 776–786. (https://doi.org/10.1002/hep.1840210327)
Huang RP, Peng A, Golard A, Hossain MZ, Huang R, Liu YG & Boynton AL 2001 Hydrogen peroxide promotes transformation of rat liver non-neoplastic epithelial cells through activation of epidermal growth factor receptor. Molecular Carcinogenesis 30 209–217. (https://doi.org/10.1002/mc.1030)
Jakubowski A, Ambrose C, Parr M, Lincecum JM, Wang MZ, Zheng TS, Browning B, Michaelson JS, Baetscher M, Wang B, et al.2005 TWEAK induces liver progenitor cell proliferation. Journal of Clinical Investigation 115 2330–2340. (https://doi.org/10.1172/JCI23486)
Jungermann K & Kietzmann T 1996 Zonation of parenchymal and nonparenchymal metabolism in liver. Annual Review of Nutrition 16 179–203. (https://doi.org/10.1146/annurev.nu.16.070196.001143)
Kalen A, Appelkvist EL & Dallner G 1987 Biosynthesis of ubiquinone in rat liver. Acta Chemica Scandinavica. Series B 41 70–72. (https://doi.org/10.3891/acta.chem.scand.41b-0070)
Kamata H, Oka S, Shibukawa Y, Kakuta J & Hirata H 2005 Redox regulation of nerve growth factor-induced neuronal differentiation of PC12 cells through modulation of the nerve growth factor receptor, TrkA. Archives of Biochemistry and Biophysics 434 16–25. (https://doi.org/10.1016/j.abb.2004.07.036)
Katsuyama M 2010 NOX/NADPH oxidase, the superoxide-generating enzyme: its transcriptional regulation and physiological roles. Journal of Pharmacological Sciences 114 134–146. (https://doi.org/10.1254/jphs.10r01cr)
Kietzmann T 2017 Metabolic zonation of the liver: the oxygen gradient revisited. Redox Biology 11 622–630. (https://doi.org/10.1016/j.redox.2017.01.012)
Kim TH, Mars WM, Stolz DB, Petersen BE & Michalopoulos GK 1997 Extracellular matrix remodeling at the early stages of liver regeneration in the rat. Hepatology 26 896–904. (https://doi.org/10.1002/hep.510260415)
Kretzschmar M 1996 Regulation of hepatic glutathione metabolism and its role in hepatotoxicity. Experimental and Toxicologic Pathology 48 439–446. (https://doi.org/10.1016/S0940-2993(9680054-6)
Kron P, Linecker M, Limani P, Schlegel A, Kambakamba P, Lehn JM, Nicolau C, Graf R, Humar B & Clavien PA 2016 Hypoxia-driven Hif2a coordinates mouse liver regeneration by coupling parenchymal growth to vascular expansion. Hepatology 64 2198–2209. (https://doi.org/10.1002/hep.28809)
Lindroos PM, Zarnegar R & Michalopoulos GK 1991 Hepatocyte growth factor (hepatopoietin A) rapidly increases in plasma before DNA synthesis and liver regeneration stimulated by partial hepatectomy and carbon tetrachloride administration. Hepatology 13 743–750. (https://doi.org/10.1002/hep.1840130422)
Liu X & Green RM 2019 Endoplasmic reticulum stress and liver diseases. Liver Research 3 55–64. (https://doi.org/10.1016/j.livres.2019.01.002)
Lukacs-Kornek V & Lammert F 2017 The progenitor cell dilemma: cellular and functional heterogeneity in assistance or escalation of liver injury. Journal of Hepatology 66 619–630. (https://doi.org/10.1016/j.jhep.2016.10.033)
Madrigal-Matute J & Cuervo AM 2016 Regulation of liver metabolism by autophagy. Gastroenterology 150 328–339. (https://doi.org/10.1053/j.gastro.2015.09.042)
Maeno H, Ono T, Dhar DK, Sato T, Yamanoi A & Nagasue N 2005 Expression of hypoxia inducible factor-1alpha during liver regeneration induced by partial hepatectomy in rats. Liver International 25 1002–1009. (https://doi.org/10.1111/j.1478-3231.2005.01144.x)
Malhotra JD & Kaufman RJ 2007 Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxidants and Redox Signaling 9 2277–2293. (https://doi.org/10.1089/ars.2007.1782)
Mari M, Colell A, Morales A, von Montfort C, Garcia-Ruiz C & Fernandez-Checa JC 2010 Redox control of liver function in health and disease. Antioxidants and Redox Signaling 12 1295–1331. (https://doi.org/10.1089/ars.2009.2634)
Marklund S 1980 Distribution of CuZn superoxide dismutase and Mn superoxide dismutase in human tissues and extracellular fluids. Acta Physiologica Scandinavica. Supplementum 492 19–23.
Marshall A, Rushbrook S, Davies SE, Morris LS, Scott IS, Vowler SL, Coleman N & Alexander G 2005 Relation between hepatocyte G1 arrest, impaired hepatic regeneration, and fibrosis in chronic hepatitis C virus infection. Gastroenterology 128 33–42. (https://doi.org/10.1053/j.gastro.2004.09.076)
Medina J & Moreno-Otero R 2005 Pathophysiological basis for antioxidant therapy in chronic liver disease. Drugs 65 2445–2461. (https://doi.org/10.2165/00003495-200565170-00003)
Michalopoulos GK 2007 Liver regeneration. Journal of Cellular Physiology 213 286–300. (https://doi.org/10.1002/jcp.21172)
Michalopoulos GK 2013 Principles of liver regeneration and growth homeostasis. Comprehensive Physiology 3 485–513. (https://doi.org/10.1002/cphy.c120014)
Michalopoulos GK & Khan Z 2015 Liver stem cells: experimental findings and implications for human liver disease. Gastroenterology 149 876–882. (https://doi.org/10.1053/j.gastro.2015.08.004)
Michalopoulos GK & Bhushan B 2021 Liver regeneration: biological and pathological mechanisms and implications. Nature Reviews: Gastroenterology and Hepatology 18 40–55. (https://doi.org/10.1038/s41575-020-0342-4)
Michelotti GA, Tucker A, Swiderska-Syn M, Machado MV, Choi SS, Kruger L, Soderblom E, Thompson JW, Mayer-Salman M, Himburg HA, et al.2016 Pleiotrophin regulates the ductular reaction by controlling the migration of cells in liver progenitor niches. Gut 65 683–692. (https://doi.org/10.1136/gutjnl-2014-308176)
Miller CG & Schmidt EE 2019 Disulfide reductase systems in liver. British Journal of Pharmacology 176 532–543. (https://doi.org/10.1111/bph.14498)
Minocha S, Villeneuve D, Rib L, Moret C, Guex N & Herr W 2017 Segregated hepatocyte proliferation and metabolic states within the regenerating mouse liver. Hepatology Communications 1 871–885. (https://doi.org/10.1002/hep4.1102)
Miyajima A, Tanaka M & Itoh T 2014 Stem/progenitor cells in liver development, homeostasis, regeneration, and reprogramming. Cell Stem Cell 14 561–574. (https://doi.org/10.1016/j.stem.2014.04.010)
Miyazaki Y, Shinomura Y, Tsutsui S, Yasunaga Y, Zushi S, Higashiyama S, Taniguchi N & Matsuzawa Y 1996 Oxidative stress increases gene expression of heparin-binding EGF-like growth factor and amphiregulin in cultured rat gastric epithelial cells. Biochemical and Biophysical Research Communications 226 542–546. (https://doi.org/10.1006/bbrc.1996.1391)
Morales-González Á, Bautista M, Madrigal-Santillan E, Posadas-Mondragon A, Anguiano-Robledo L, Madrigal-Bujadar E, Alvarez-Gonzalez I, Fregoso-Aguilar T, Gayosso-Islas E, Sanchez-Moreno C, et al.2017 Nrf2 modulates cell proliferation and antioxidants defenses during liver regeneration induced by partial hepatectomy. International Journal of Clinical and Experimental Pathology 10 7801–7811.(https://pubmed.ncbi.nlm.nih.gov/31966628/)
Moreno-Sanchez R, Hernandez-Esquivel L, Rivero-Segura NA, Marin-Hernandez A, Neuzil J, Ralph SJ & Rodriguez-Enriquez S 2013 Reactive oxygen species are generated by the respiratory complex II--evidence for lack of contribution of the reverse electron flow in complex I. FEBS Journal 280 927–938. (https://doi.org/10.1111/febs.12086)
Morsiani E, Aleotti A & Ricci D 1998 Haemodynamic and ultrastructural observations on the rat liver after two-thirds partial hepatectomy. Journal of Anatomy 192 507–515. (https://doi.org/10.1046/j.1469-7580.1998.19240507.x)
Mracek T, Pecinova A, Vrbacky M, Drahota Z & Houstek J 2009 High efficiency of ROS production by glycerophosphate dehydrogenase in mammalian mitochondria. Archives of Biochemistry and Biophysics 481 30–36. (https://doi.org/10.1016/j.abb.2008.10.011)
Mullen L, Mengozzi M, Hanschmann EM, Alberts B & Ghezzi P 2020 How the redox state regulates immunity. Free Radical Biology and Medicine 157 3–14. (https://doi.org/10.1016/j.freeradbiomed.2019.12.022)
Nejak-Bowen K 2020 If it looks like a duct and acts like a duct: on the role of reprogrammed hepatocytes in cholangiopathies. Gene Expression 20 19–23. (https://doi.org/10.3727/105221619X15664105014956)
Nishino H & Ito A 1986 Subcellular distribution of OM cytochrome b-mediated NADH-semidehydroascorbate reductase activity in rat liver. Journal of Biochemistry 100 1523–1531. (https://doi.org/10.1093/oxfordjournals.jbchem.a121859)
Nohl H & Gille L 2002 The bifunctional activity of ubiquinone in lysosomal membranes. Biogerontology 3 125–131. (https://doi.org/10.1023/a:1015288220217)
Oh SH, Swiderska-Syn M, Jewell ML, Premont RT & Diehl AM 2018 Liver regeneration requires Yap1-TGFbeta-dependent epithelial-mesenchymal transition in hepatocytes. Journal of Hepatology 69 359–367. (https://doi.org/10.1016/j.jhep.2018.05.008)
Okado-Matsumoto A & Fridovich I 2001 Subcellular distribution of superoxide dismutases (SOD) in rat liver: Cu,Zn-SOD in mitochondria. Journal of Biological Chemistry 276 38388–38393. (https://doi.org/10.1074/jbc.M105395200)
Okuyama H, Son A, Ahsan MK, Masutani H, Nakamura H & Yodoi J 2008 Thioredoxin and thioredoxin binding protein 2 in the liver. IUBMB Life 60 656–660. (https://doi.org/10.1002/iub.102)
Olazabal IM, Munoz JA, Rodriguez-Navas C, Alvarez L, Delgado-Baeza E & Garcia-Ruiz JP 2009 Prolactin's role in the early stages of liver regeneration in rats. Journal of Cellular Physiology 219 626–633. (https://doi.org/10.1002/jcp.21707)
Oldford C, Kuksal N, Gill R, Young A & Mailloux RJ 2019 Estimation of the hydrogen peroxide producing capacities of liver and cardiac mitochondria isolated from C57BL/6N and C57BL/6J mice. Free Radical Biology and Medicine 135 15–27. (https://doi.org/10.1016/j.freeradbiomed.2019.02.012)
Overi D, Carpino G, Franchitto A, Onori P & Gaudio E 2020 Hepatocyte injury and hepatic stem cell niche in the progression of non-alcoholic steatohepatitis. Cells 9 590. (https://doi.org/10.3390/cells9030590)
Patel SH, Camargo FD & Yimlamai D 2017 Hippo signaling in the liver regulates organ size, cell fate, and carcinogenesis. Gastroenterology 152 533–545. (https://doi.org/10.1053/j.gastro.2016.10.047)
Pepe-Mooney BJ, Dill MT, Alemany A, Ordovas-Montanes J, Matsushita Y, Rao A, Sen A, Miyazaki M, Anakk S, Dawson PA, et al.2019 Single-cell analysis of the liver epithelium reveals dynamic heterogeneity and an essential role for YAP in homeostasis and regeneration. Cell Stem Cell 25 23 .e8–38.e8. (https://doi.org/10.1016/j.stem.2019.04.004)
Pizzinat N, Copin N, Vindis C, Parini A & Cambon C 1999 Reactive oxygen species production by monoamine oxidases in intact cells. Naunyn-Schmiedeberg’s Archives of Pharmacology 359 428–431. (https://doi.org/10.1007/pl00005371)
Planas-Paz L, Sun T, Pikiolek M, Cochran NR, Bergling S, Orsini V, Yang Z, Sigoillot F, Jetzer J, Syed M, et al.2019 YAP, but not RSPO-LGR4/5, signaling in biliary epithelial cells promotes a ductular reaction in response to liver injury. Cell Stem Cell 25 39 .e10–53.e10. (https://doi.org/10.1016/j.stem.2019.04.005)
Pohl C & Dikic I 2019 Cellular quality control by the ubiquitin-proteasome system and autophagy. Science 366 818–822. (https://doi.org/10.1126/science.aax3769)
Quinlan CL, Perevoshchikova IV, Hey-Mogensen M, Orr AL & Brand MD 2013 Sites of reactive oxygen species generation by mitochondria oxidizing different substrates. Redox Biology 1 304–312. (https://doi.org/10.1016/j.redox.2013.04.005)
Rabinowitz JD & White E 2010 Autophagy and metabolism. Science 330 1344–1348. (https://doi.org/10.1126/science.1193497)
Raven A, Lu WY, Man TY, Ferreira-Gonzalez S, O'Duibhir E, Dwyer BJ, Thomson JP, Meehan RR, Bogorad R, Koteliansky V, et al.2017 Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration. Nature 547 350–354. (https://doi.org/10.1038/nature23015)
Reventun P, Alique M, Cuadrado I, Marquez S, Toro R, Zaragoza C & Saura M 2017 iNOS-derived nitric oxide induces integrin-linked kinase endocytic lysosome-mediated degradation in the vascular endothelium. Arteriosclerosis, Thrombosis, and Vascular Biology 37 1272–1281. (https://doi.org/10.1161/ATVBAHA.117.309560)
Rhee SG, Woo HA & Kang D 2018 The role of peroxiredoxins in the transduction of H2O2 signals. Antioxidants and Redox Signaling 28 537–557. (https://doi.org/10.1089/ars.2017.7167)
Rokka A, Antonenkov VD, Soininen R, Immonen HL, Pirila PL, Bergmann U, Sormunen RT, Weckstrom M, Benz R & Hiltunen JK 2009 Pxmp2 is a channel-forming protein in Mammalian peroxisomal membrane. PLoS ONE 4 e5090. (https://doi.org/10.1371/journal.pone.0005090)
Romero-Gallo J, Sozmen EG, Chytil A, Russell WE, Whitehead R, Parks WT, Holdren MS, Her MF, Gautam S, Magnuson M, et al.2005 Inactivation of TGF-beta signaling in hepatocytes results in an increased proliferative response after partial hepatectomy. Oncogene 24 3028–3041. (https://doi.org/10.1038/sj.onc.1208475)
Roskams T 2006 Different types of liver progenitor cells and their niches. Journal of Hepatology 45 1–4. (https://doi.org/10.1016/j.jhep.2006.05.002)
Rudolph KL, Trautwein C, Kubicka S, Rakemann T, Bahr MJ, Sedlaczek N, Schuppan D & Manns MP 1999 Differential regulation of extracellular matrix synthesis during liver regeneration after partial hepatectomy in rats. Hepatology 30 1159–1166. (https://doi.org/10.1002/hep.510300502)
Rui L 2014 Energy metabolism in the liver. Comprehensive Physiology 4 177–197. (https://doi.org/10.1002/cphy.c130024)
Russell WE, Coffey Jr. R, Ouellette AJ & Moses HL 1988 Type beta transforming growth factor reversibly inhibits the early proliferative response to partial hepatectomy in the rat. PNAS 85 5126–5130. (https://doi.org/10.1073/pnas.85.14.5126)
Saito A, Hayashi T, Okuno S, Nishi T & Chan PH 2004 Oxidative stress affects the integrin-linked kinase signaling pathway after transient focal cerebral ischemia. Stroke 35 2560–2565. (https://doi.org/10.1161/01.STR.0000144653.32853.ed)
Samhan-Arias AK & Gutierrez-Merino C 2014 Purified NADH-cytochrome b5 reductase is a novel superoxide anion source inhibited by apocynin: sensitivity to nitric oxide and peroxynitrite. Free Radical Biology and Medicine 73 174–189. (https://doi.org/10.1016/j.freeradbiomed.2014.04.033)
Schadde E, Tsatsaris C, Swiderska-Syn M, Breitenstein S, Urner M, Schimmer R, Booy C, Z'graggen BR, Wenger RH, Spahn DR, et al.2017 Hypoxia of the growing liver accelerates regeneration. Surgery 161 666–679. (https://doi.org/10.1016/j.surg.2016.05.018)
Schaub JR, Malato Y, Gormond C & Willenbring H 2014 Evidence against a stem cell origin of new hepatocytes in a common mouse model of chronic liver injury. Cell Reports 8 933–939. (https://doi.org/10.1016/j.celrep.2014.07.003)
Schwabe RF & Brenner DA 2006 Mechanisms of liver injury. I. TNF-alpha-induced liver injury: role of IKK, JNK, and ROS pathways. American Journal of Physiology: Gastrointestinal and Liver Physiology 290 G583–G589. (https://doi.org/10.1152/ajpgi.00422.2005)
Sell S 1998 Comparison of liver progenitor cells in human atypical ductular reactions with those seen in experimental models of liver injury. Hepatology 27 317–331. (https://doi.org/10.1002/hep.510270202)
Senoner T, Schindler S, Stattner S, Ofner D, Troppmair J & Primavesi F 2019 Associations of oxidative stress and postoperative outcome in liver surgery with an outlook to future potential therapeutic options. Oxidative Medicine and Cellular Longevity 2019 3950818. (https://doi.org/10.1155/2019/3950818)
Serviddio G, Bellanti F & Vendemiale G 2013 Free radical biology for medicine: learning from nonalcoholic fatty liver disease. Free Radical Biology and Medicine 65 952–968. (https://doi.org/10.1016/j.freeradbiomed.2013.08.174)
Sies H 2015 Oxidative stress: a concept in redox biology and medicine. Redox Biology 4 180–183. (https://doi.org/10.1016/j.redox.2015.01.002)
Sies H 2020 Findings in redox biology: From H2O2 to oxidative stress. Journal of Biological Chemistry 295 13458–13473. (https://doi.org/10.1074/jbc.X120.015651)
Singla A, Moons DS, Snider NT, Wagenmaker ER, Jayasundera VB & Omary MB 2012 Oxidative stress, Nrf2 and keratin up-regulation associate with Mallory-Denk body formation in mouse erythropoietic protoporphyria. Hepatology 56 322–331. (https://doi.org/10.1002/hep.25664)
Smyrniotis V, Kostopanagiotou G, Kondi A, Gamaletsos E, Theodoraki K, Kehagias D, Mystakidou K & Contis J 2002 Hemodynamic interaction between portal vein and hepatic artery flow in small-for-size split liver transplantation. Transplant International 15 355–360. (https://doi.org/10.1007/s00147-002-0425-x)
So J, Kim A, Lee SH & Shin D 2020 Liver progenitor cell-driven liver regeneration. Experimental and Molecular Medicine 52 1230–1238. (https://doi.org/10.1038/s12276-020-0483-0)
Stanger BZ 2015 Cellular homeostasis and repair in the mammalian liver. Annual Review of Physiology 77 179–200. (https://doi.org/10.1146/annurev-physiol-021113-170255)
Stankova P, Kucera O, Lotkova H, Rousar T, Endlicher R & Cervinkova Z 2010 The toxic effect of thioacetamide on rat liver in vitro. Toxicology in Vitro 24 2097–2103. (https://doi.org/10.1016/j.tiv.2010.06.011)
Stirpe F, Ravaioli M, Battelli MG, Musiani S & Grazi GL 2002 Xanthine oxidoreductase activity in human liver disease. American Journal of Gastroenterology 97 2079–2085. (https://doi.org/10.1111/j.1572-0241.2002.05925.x)
Swiderska-Syn M, Xie G, Michelotti GA, Jewell ML, Premont RT, Syn WK & Diehl AM 2016 Hedgehog regulates yes-associated protein 1 in regenerating mouse liver. Hepatology 64 232–244. (https://doi.org/10.1002/hep.28542)
Tajima T, Goda N, Fujiki N, Hishiki T, Nishiyama Y, Senoo-Matsuda N, Shimazu M, Soga T, Yoshimura Y, Johnson RS, et al.2009 HIF-1alpha is necessary to support gluconeogenesis during liver regeneration. Biochemical and Biophysical Research Communications 387 789–794. (https://doi.org/10.1016/j.bbrc.2009.07.115)
Tao GZ, Lehwald N, Jang KY, Baek J, Xu B, Omary MB & Sylvester KG 2013 Wnt/beta-catenin signaling protects mouse liver against oxidative stress-induced apoptosis through the inhibition of forkhead transcription factor FoxO3. Journal of Biological Chemistry 288 17214–17224. (https://doi.org/10.1074/jbc.M112.445965)
Tarlow BD, Finegold MJ & Grompe M 2014a Clonal tracing of Sox9+ liver progenitors in mouse oval cell injury. Hepatology 60 278–289. (https://doi.org/10.1002/hep.27084)
Tarlow BD, Pelz C, Naugler WE, Wakefield L, Wilson EM, Finegold MJ & Grompe M 2014b Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes. Cell Stem Cell 15 605–618. (https://doi.org/10.1016/j.stem.2014.09.008)
Taylor BS, Alarcon LH & Billiar TR 1998 Inducible nitric oxide synthase in the liver: regulation and function. Biochemistry. Biokhimiia 63 766–781.
Tikhanovich I, Cox J & Weinman SA 2013 Forkhead box class O transcription factors in liver function and disease. Journal of Gastroenterology and Hepatology 28 (Supplement 1) 125–131. (https://doi.org/10.1111/jgh.12021)
Toppo S, Vanin S, Bosello V & Tosatto SC 2008 Evolutionary and structural insights into the multifaceted glutathione peroxidase (Gpx) superfamily. Antioxidants and Redox Signaling 10 1501–1514. (https://doi.org/10.1089/ars.2008.2057)
Wang Y & Hekimi S 2016 Understanding ubiquinone. Trends in Cell Biology 26 367–378. (https://doi.org/10.1016/j.tcb.2015.12.007)
Wang Y, Li J, Gao Y, Luo Y, Luo H, Wang L, Yi Y, Yuan Z & Jim Xiao ZX 2019 Hippo kinases regulate cell junctions to inhibit tumor metastasis in response to oxidative stress. Redox Biology 26 101233. (https://doi.org/10.1016/j.redox.2019.101233)
Watmough NJ & Frerman FE 2010 The electron transfer flavoprotein: ubiquinone oxidoreductases. Biochimica et Biophysica Acta 1797 1910–1916. (https://doi.org/10.1016/j.bbabio.2010.10.007)
Weng HL, Cai X, Yuan X, Liebe R, Dooley S, Li H & Wang TL 2015 Two sides of one coin: massive hepatic necrosis and progenitor cell-mediated regeneration in acute liver failure. Frontiers in Physiology 6 178. (https://doi.org/10.3389/fphys.2015.00178)
Wruck CJ, Streetz K, Pavic G, Gotz ME, Tohidnezhad M, Brandenburg LO, Varoga D, Eickelberg O, Herdegen T, Trautwein C, et al.2011 Nrf2 induces interleukin-6 (IL-6) expression via an antioxidant response element within the IL-6 promoter. Journal of Biological Chemistry 286 4493–4499. (https://doi.org/10.1074/jbc.M110.162008)
Wu H, Xiao Y, Zhang S, Ji S, Wei L, Fan F, Geng J, Tian J, Sun X, Qin F, et al.2013 The Ets transcription factor GABP is a component of the hippo pathway essential for growth and antioxidant defense. Cell Reports 3 1663–1677. (https://doi.org/10.1016/j.celrep.2013.04.020)
Xiao JC, Ruck P, Adam A, Wang TX & Kaiserling E 2003 Small epithelial cells in human liver cirrhosis exhibit features of hepatic stem-like cells: immunohistochemical, electron microscopic and immunoelectron microscopic findings. Histopathology 42 141–149. (https://doi.org/10.1046/j.1365-2559.2003.01544.x)
Xiao W, Wang RS, Handy DE & Loscalzo J 2018 NAD(H) and NADP(H) redox couples and cellular energy metabolism. Antioxidants and Redox Signaling 28 251–272. (https://doi.org/10.1089/ars.2017.7216)
Yamada Y, Webber EM, Kirillova I, Peschon JJ & Fausto N 1998 Analysis of liver regeneration in mice lacking type 1 or type 2 tumor necrosis factor receptor: requirement for type 1 but not type 2 receptor. Hepatology 28 959–970. (https://doi.org/10.1002/hep.510280410)
Yang J, Mowry LE, Nejak-Bowen KN, Okabe H, Diegel CR, Lang RA, Williams BO & Monga SP 2014 2014 beta-catenin signaling in murine liver zonation and regeneration: a Wnt-Wnt situation! Hepatology 60 964–976. (https://doi.org/10.1002/hep.27082)
Yanger K, Zong Y, Maggs LR, Shapira SN, Maddipati R, Aiello NM, Thung SN, Wells RG, Greenbaum LE & Stanger BZ 2013 Robust cellular reprogramming occurs spontaneously during liver regeneration. Genes and Development 27 719–724. (https://doi.org/10.1101/gad.207803.112)
Yanger K & Stanger BZ 2014 Liver cell reprogramming: parallels with iPSC biology. Cell Cycle 13 1211–1212. (https://doi.org/10.4161/cc.28381)
Yimlamai D, Christodoulou C, Galli GG, Yanger K, Pepe-Mooney B, Gurung B, Shrestha K, Cahan P, Stanger BZ & Camargo FD 2014 Hippo pathway activity influences liver cell fate. Cell 157 1324–1338. (https://doi.org/10.1016/j.cell.2014.03.060)
Zeeshan HM, Lee GH, Kim HR & Chae HJ 2016 Endoplasmic reticulum stress and associated ROS. International Journal of Molecular Sciences 17 327. (https://doi.org/10.3390/ijms17030327)
Zeng W, Xiao J, Zheng G, Xing F, Tipoe GL, Wang X, He C, Chen ZY & Liu Y 2015 Antioxidant treatment enhances human mesenchymal stem cell anti-stress ability and therapeutic efficacy in an acute liver failure model. Scientific Reports 5 11100. (https://doi.org/10.1038/srep11100)
Zhan SS, Jiang JX, Wu J, Halsted C, Friedman SL, Zern MA & Torok NJ 2006 Phagocytosis of apoptotic bodies by hepatic stellate cells induces NADPH oxidase and is associated with liver fibrosis in vivo. Hepatology 43 435–443. (https://doi.org/10.1002/hep.21093)
Zorov DB, Juhaszova M & Sollott SJ 2014 Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiological Reviews 94 909–950. (https://doi.org/10.1152/physrev.00026.2013)
