Impaired Liver Regeneration Research Articles

Overall Body Composition and Sarcopenia Are Associated with Poor Liver Hypertrophy Following Portal Vein Embolization

PurposeTo explore whether body composition and/or sarcopenia are associated with liver hypertrophy following portal vein embolization (PVE) in patients with colorectal liver metastases (CLM). MethodsPatients with CLM who underwent right PVE prior to a planned right hepatectomy were identified from the institutional liver database from 2004 to 2014. Patients were excluded due to previous liver-directed therapy/hepatectomy, right PVE + segment IV embolization, or planned 2-stage hepatectomy. Advanced imaging software was used to measure body compartment volumes (cm2), which were standardized to height (m2) to create an index: skeletal muscle index (SMI), subcutaneous adipose index (SAI), and visceral adipose index (VAI). SMI, gender, and body mass index (BMI) were used to define sarcopenia. The main outcome of interest was hypertrophy of the future liver remnant (FLR) following PVE, which was reported as degree of hypertrophy (DH) and kinetic growth rate (KGR). ResultsPatients were evenly divided into three KGR groups: lower third (KGR:0.7–2.0%), middle third (KGR:2.0–4.1%), and upper third (KGR:4.2–12.3%). Patients in the lower third KGR group had a lower VAI (31.0 vs 53.0 vs 54.5 cm2/m2, p = 0.042) and were more commonly sarcopenic (60%) compared to the upper third (20%, p = 0.025). Eighteen patients (40%) met criteria for sarcopenia. Sarcopenic patients had a lower VAI (29.1 vs 57.4 cm2/m2, p = 0.004), lesser degree of hypertrophy (8.3% vs 15.2%, p = 0.009), and lower KGR (2.0% vs 4.0%, p = 0.012). ConclusionSarcopenia and associated body composition indices are strongly associated with clinically relevant impaired liver regeneration, which may result in increased liver-specific complications following hepatectomy for CLM.

Translationally controlled tumor protein promotes liver regeneration by activating mTORC2/AKT signaling

Translationally controlled tumor protein (TCTP), which is a protein characterized by its potent proliferation promoting activity, has been well studied in the area of growth and tumorigenesis. However, the specific role of TCTP in liver regeneration (LR) and its underlying mechanism remains unclear. In order to investigate the contribution of TCTP during LR, heterozygous TCTP mice were generated, and a mimic LR model was applied to TCTP-knockdown (KD) hepatic cell lines. The results revealed that TCTP-KD impaired LR in mice, and manifested as the following aspects: delayed proliferation of hepatocytes, accompanied by disruption of the mRNA expression of markers of the cell cycle, degenerated lipid metabolism, and abnormal immune response. Furthermore, it was found out that TCTP activated PI3K/AKT signaling by regulating mTORC2. Lastly, the increasing rate of serum TCTP positively correlated to the recovery of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) after liver resection in humans. In summary, the present study is the first to reveal the crucial role of intracellular TCTP in LR.

Interleukin-22 ameliorates acute-on-chronic liver failure by reprogramming impaired regeneration pathways in mice

Acute-on-chronic liver failure (ACLF) is a clinical syndrome defined by liver failure on pre-existing chronic liver disease. It is often associated with bacterial infection and high short-term mortality. Experimental models that fully reproduce ACLF are lacking, so too are effective pharmacological therapies for this condition. To mimic ACLF conditions, we developed a severe liverinjury model by combining chronic injury (chronic carbon tetrachloride [CCl4] injection), acute hepatic insult (injection of adouble dose of CCl4), and bacterial infection (intraperitoneal injection of bacteria). Serum and liver samples from patients with ACLF or acute drug-induced liver injury (DILI) were used. Liver injury and regeneration were assessed to ascertain the potential benefits of interleukin-22 (IL-22Fc) administration. This severe liver injury model recapitulated some of the key features of clinical ACLF, including acute-on-chronic liver injury, bacterial infection, multi-organ injury, and high mortality. Liver regeneration in this model was severely impaired because of a shift from the activation of the pro-regenerative IL-6/STAT3 pathway to the anti-regenerative IFN-γ/STAT1 pathway. The impaired IL-6/STAT3 activation was due to the inability of Kupffer cells to produce IL-6; whereas the enhanced STAT1 activation was due to a strong innate immune response and subsequent production of IFN-γ. Compared to patients with DILI, patients with ACLF had higher levels of IFN-γ but lower liver regeneration. IL-22Fc treatment improved survival in ACLF mice by reversing the STAT1/STAT3 pathway imbalance and enhancing expression of many antibacterial genes in a manner involving the anti-apoptotic protein BCL2. Acute-on-chronic liver injury or bacterial infection is associated with impaired liver regeneration due to a shift from a pro-regenerative to an anti-regenerative pathway. IL-22Fc therapy reverses this shift and attenuates bacterial infection, thus IL-22Fc may have therapeutic potential for ACLF treatment. A mouse model combining chronic liver injury, acute hepatic insult, and bacterial infection recapitulates some ofthe key features of acute-on-chronic liver failure (ACLF) in patients. Both fibrosis and bacterial infection contribute to theimpaired regenerative capacity of the liver in patients with ACLF. Herein, we show that IL-22Fc therapy improves ACLF by reprogramming impaired regenerative pathways and attenuating bacterial infection. Thus, it may have therapeutic potential for patients with ACLF.

Platelet and liver regeneration after liver surgery.

The success of liver surgery, including resection and transplantation, is largely dependent on the ability of the liver to regenerate. Despite substantial improvement in surgical techniques and perioperative care, one of the main concerns is post-hepatectomy liver failure and early allograft dysfunction, both of which are associated with impaired liver regeneration. Recent studies have demonstrated the positive role of platelets in promoting liver regeneration and protecting hepatocytes; however, the underlying mechanisms responsible for these effects are not fully understood. In this review, we updated the accumulated evidence of the role of platelets in promoting liver regeneration, with a focus on liver resection and liver transplantation. The goal of these studies was to support the clinical implementation of platelet agents, such as thrombopoietin receptor agonists, to augment liver regeneration after liver surgery. This "platelet therapy" may become a treatment choice for post-hepatectomy liver failure and early allograft dysfunction.

Effectiveness of terlipressin for prevention of complications after major liver resection – A randomized placebo-controlled trial

BackgroundElevated portal pressure in response to major liver resection is associated with impaired liver regeneration and increased postoperative complications. Terlipressin, a splanchnic vasoconstrictor used for treatment of hepatorenal syndrome, was tested for reduction of complications and renal protection after liver resection. MethodsA randomized double-blinded placebo-controlled trial including patients undergoing elective major liver resection was performed. Terlipressin was administered to patients in the intervention group for five days. The primary outcome parameter was the incidence of a clinical composite endpoint of following liver specific complications 6 weeks after surgery: liver failure, ascites, bile leakage, intra-abdominal abscess and operative mortality. Postoperative kidney function was assessed as a secondary endpoint. Results150 patients (mean age 63.4 years, 73.3% male) were included. No difference was found in the composite endpoint between the placebo and intervention group (32.8% versus 30.8%, relative risk 1.066, 95%CI 0.643 to 1.769, p = 0.85). Patients receiving terlipressin showed a significant lower decrease in postoperative estimated glomerular filtration rate compared to placebo (two way ANOVA, p = 0.005). ConclusionPerioperative administration of terlipressin during major liver surgery did not affect a composite endpoint of liver specific complications, but significantly protected from postoperative deterioration of kidney function compared to placebo. Clinicaltrials.gov identifierNCT01921985.

GDF11 impairs liver regeneration in mice after partial hepatectomy.

Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor (TGF)-β superfamily. The rejuvenative effect of GDF11 has been called into question recently, and its role in liver regeneration is unclear. Here, we investigated the pathophysiologic role of GDF11, as well as its plausible signaling mechanisms in a mouse model of partial hepatectomy (PH). We demonstrated that both serum and hepatic GDF11 protein expression increased following PH. Treatment with adeno-associated viruses-GDF11 and recombinant GDF11 protein severely impaired liver regeneration, whereas inhibition of GDF11 activity with neutralizing antibodies significantly improved liver regeneration after PH. In vitro, GDF11 treatment significantly delayed cell proliferation and induced cell-cycle arrest in α mouse liver 12 (AML12) cells. Moreover, GDF11 activated TGF-β-SMAD2/3 signaling pathway. Inhibition of GDF11-induced SMAD2/3 activity significantly blocked GDF11-mediated reduction in cell proliferation both in vivo and in vitro. In the clinical setting, GDF11 levels were significantly elevated in patients after hepatectomy. Collectively, these results indicate that rather than a 'rejuvenating' agent, GDF11 impairs liver regeneration after PH. Suppression of cell-cycle progression via TGF-β-SMAD2/3 signaling pathway may be a key mechanism by which GDF11 inhibits liver regeneration.

Dicer1 facilitates liver regeneration in a manner dependent on the inhibitory effect of miR-21 on Pten and Rhob expression

AimsTamoxifen-induced liver-specific Dicer1 deletion (iDicer1−/−) in mature mice may provide clues demonstrating the genuine effects of acute loss of Dicer1 and miRNAs in the liver regeneration process. Main methodsIn this study, mice with tamoxifen-induced Dicer1 deletion through the Cre/LoxP system were constructed and then underwent classic 70% partial hepatectomy or CCl4-induced liver injury. To rescue the inhibitory effect of Dicer1 ablation on liver regeneration, miR-21 agomir was injected into the tail vein of iDicer1−/− mice. Key findingsUnlike constitutive embryonic deletion of Dicer1, tamoxifen-induced Dicer1 deletion did not result in severe liver injury or lesions, providing an ideal model for investigating acute loss of Dicer1 and miRNAs in liver regeneration. Dicer1 deletion led to impaired liver regeneration through the inhibitory effect of miR-21 on PTEN and Rhob expression. SignificanceIn our previous study, we found that embryonic loss of Dicer1 impairs hepatocyte survival and leads to chronic inflammation and progenitor cell activation, while the role of Dicer1 in liver regeneration remains largely unknown. We clearly identified the promotion effect of Dicer1 on liver regeneration by increasing miR-21 expression, which inhibits the expression of two negative cell proliferation regulators, Pten and Rhob.

A Homeostatic Arid1a-Dependent Permissive Chromatin State Licenses Hepatocyte Responsiveness to Liver-Injury-Associated YAP Signaling

Following injury, differentiated epithelial cells can serve as a stem cell-independent source for tissue regeneration by undergoing reprogramming into other cell types. The intrinsic molecular basis underlying plasticity of differentiated cells remains largely unaddressed. Here we show that Arid1a, a key component of the SWI/SNF chromatin remodeling complex, controls liver regeneration and gene expression associated with emergence of injury-induced liver-progenitor-like cells (LPLCs). Hepatocyte-specific Arid1a ablation reduces LPLC gene expression in several models of periportal liver injury and impairs liver regeneration, leading to organ dysfunction. Arid1a establishes a permissive chromatin state at LPLC-enriched genes during homeostasis, suggesting it endows hepatocytes with competence to respond to injury-induced signals. Consistently, Arid1a facilitates binding of YAP, a critical regeneration signaling pathway, to LPLC-enriched genes, and Arid1a deletion prevents their YAP-associated induction following injury. Together, these findings provide a framework for studying the contributions of injury-induced LPLCs to periportal liver regeneration.

Estradiol accelerates liver regeneration through estrogen receptor α.

Background: We previously demonstrated that liver resection triggers estradiol production, which, in turn, induces the proliferation of hepatocytes to promote liver regeneration in mice. In this study, we demonstrated estradiol-induced estrogen receptor alpha (ERα) expression.Methods: To further explore the role of ERα in estradiol-mediated liver regeneration, in the present study, we confirmed impaired liver regeneration ability in ERα knockout mice.Results: Further analysis during liver regeneration revealed a role for ERα in hepatic steatosis, tumor necrosis factor-alpha and interleukin 6 expression, and nuclear factor-κB and signal transducer and activator of transcription 3 DNA-binding activities.Conclusion: Moreover, estradiol administration accelerated liver regeneration through ERα, indicating the feasibility of the estrogen-ERα axis as a target for accelerating the rate of liver regeneration.

FXR activation impairs liver progenitor cell‐driven liver regeneration by enhancing PTEN‐dependent inhibition of AKT‐mTOR axis

Liver progenitor cells (LPCs) are activated by liver injury and their expansion correlates with disease severity. However, the differentiation of this population into hepatocytes occurs only in extreme situations, when hepatocytes fail to proliferate or senescence, to restore hepatic mass and function. Furthermore, expanding LPCs, if unable to differentiate, can secrete pro‐inflammatory and pro‐fibrogenic cytokines and thus not only fail to contribute to recovery but may, in fact, contribute to ongoing injury in the diseased livers. Recently, promoting LPC‐driven liver regeneration has garnered attention as an alternative to liver transplantation, the only reliable treatment for patients with end‐stage liver diseases. However, the molecular mechanisms of LPC‐driven repair are largely unknown. Farnesoid X receptor (FXR) is a bile acid receptor and biological sensor for the regulation of systemic bile acid homeostasis. Activation of FXR, using synthetic agonists, has shown beneficial effects on various liver diseases, including metabolic disorders, liver regeneration, and liver cancer. Currently, obeticholic acid (OCA, selective FXR agonist) is in phase II/III clinical trials for several liver diseases, such as primary biliary cholangitis, alcoholic hepatitis, and non‐alcoholic steatohepatitis (NASH). However, no studies have addressed the role of FXR signaling in LPC‐driven liver regeneration. To investigate the effect of FXR activation on LPC‐driven liver regeneration, we utilized a zebrafish liver injury model in which the robust transition of biliary epithelial cells (BECs) into hepatocytes occurs upon pharmarcogenetic pan‐hepatocyte ablation. Intriguingly, treating hepatocyte‐ablated zebrafish larvae with the FXR agonist, GW4064, impaired LPC‐driven liver regeneration by: (1) repressing differentiation of LPCs to either hepatocytes or BECs, (2) reducing proliferation of LPC‐derived cells, and (3) inducing death of LPC–derived cells. Notably, pten expression was significantly enhanced in regenerating livers by GW4064 treatment. Intriguingly, the pharmacologic inhibition of PTEN downstream factors, PI3K, AKT, mTOR and BCL2, resulted in similar regeneration defects as observed by FXR activation. Moreover, regeneration defects observed in GW4064‐treated larvae were partially rescued in larvae co‐treated with a PTEN inhibitor and in ptena/b heterozygous mutant fish, suggesting PTEN as a key downstream mediator of FXR signaling in LPC‐driven liver regeneration. Lastly, fxr mutant fish exhibited enhanced LPC‐to‐hepatocyte differentiation compared with their wild‐type sibling fish. Collectively, our study reveals novel molecular mechanisms by which FXR activation impairs LPC‐driven liver regeneration partly by enhancing pten expression, which inhibits the AKT‐mTOR‐BCL2 axis. Thus, our results provide insights into the molecular mechanisms regulating LPC‐driven liver regeneration and lay the foundation for developing therapeutics to promote LPC differentiation in patients with advanced liver diseases.Support or Funding InformationNIH grants to D.S. (DK101426) and S.P.M. (DK62277, DK100287, CA204586). Endowed Chair for Experimental Pathology to S.P.M.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Liver-specific Sirtuin6 ablation impairs liver regeneration after 2/3 partial hepatectomy.

Sirtuin 6 (Sirt6) is an NAD+-dependent deacetylase that regulates central metabolic functions such as glucose homeostasis, fat metabolism, and cell apoptosis. However, the tissue-specific function of Sirt6 in liver regeneration remains unknown. Here, we show that liver-specific Sirt6 knockout (Sirt6LKO) impaired liver reconstitution after 2/3 partial hepatectomy, which was attributed to an alteration of cell cycle progression. Sirt6 LKO delayed hepatocyte transition into S phase during liver regeneration, as shown by the analysis of cell cycle-related proteins and the immuno staining of Ki-67 and 5-bromo-2-deoxyuridine (BrdU). The delayed cell cycle in Sirt6 LKO mice was attributed to the disruption of m-TOR and Akt activity, which is an important pro-proliferation pathway in liver regeneration. Sirt6 LKO also reduced carbon tetrachloride (CCl4 )-induced liver damage. Our results suggest that Sirt6 LKO impaired liver regeneration via delayed cell cycle and impaired m-TOR and Akt activity.

Tmub1 negatively regulates liver regeneration via inhibiting STAT3 phosphorylation

Tmub1 (transmembrane and ubiquitin-like domain-containing 1) plays negative roles in rat hepatocyte proliferation, but its underlying molecular mechanisms in liver regeneration regulation have yet to be revealed. Here, we show that in vivo transfection of Tmub1 overexpression vectors impaired mouse liver regeneration after partial hepatectomy (PHx). Loss- and gain-of-function analyses in human hepatocyte Lo2 cells indicated that Tmub1 inhibits the phosphorylation of STAT3 and the activation of STAT3 signaling. Furthermore, the inhibitory effect of Tmub1 overexpression on hepatocyte proliferation can be reversed by the STAT3 activator OSM, while the promotive effect of Tmub1 knockdown can be abolished by the STAT3 inhibitor stattic. Coimmunoprecipitation assays revealed interaction between Tmub1 and STAT3. Finally, we present data from chromatin immunoprecipitation and luciferase reporter gene assays and report that STAT3 binds to and activates the promoter of Tmub1, suggesting a putative negative feedback loop between Tmub1 and STAT3 signaling. Taken together, the results of our study suggest that Tmub1 is an important negative regulator of hepatocyte proliferation in liver regeneration through STAT3 signaling. These findings provide a potential strategy for the management of liver regeneration.

The absence of the adaptor proteins CARDIF/STING negatively regulates the prolfieration of liver regeneration after partial hepatectomy in mice

Background: Nucleic acid sensors are known to play a major role during liver regeneration, however, there is only limited knowledge on the role of central adaptor proteins, such as CARDIF and STING. Our hypothesis states that these modulators of the innate immune system have an influence on liver regeneration. Methods: We use a newly established CARDIF/STING knockout mouse model and a C57BL/6 control cohort. A 2/3 partial hepatectomy (PH) was performed in both groups (n=60 mice in total). Liver regeneration was quantified by liver-to-body weight ratio, proliferation was determined by BrdU staining, RNA- and protein levels of proliferation markers were analyzed in resected tissues and pro-inflammatory cytokines were measured in murine serum. Results: CARDIF/STING knockout mice showed a significantly impaired liver regeneration after PH. Expression analysis of Interleukin-6 revealed a significant decrease in the wild type cohort after PH. In CARDIF/STING knockout mice, the proliferation marker Cyclin D1 was decreased until 24 hours after surgery, while p21Cip1 expression was increased 8h post-PH. Conclusion: Together, these data provide the first experimental evidence that CARDIF/STING knockout mice show a delayed liver regeneration. In the absence of these two proteins, we observed a modulated immune response which lead to a negative regulation of the proliferative capacity after partial hepatectomy. This finding could impact on the future development of molecular therapies making use of the innate immune system.

The absence of the adaptor proteins CARDIF/STING negatively regulates the prolfieration of liver regeneration after partial hepatectomy in mice

Background: Nucleic acid sensors are known to play a major role during liver regeneration, however, there is only limited knowledge on the role of central adaptor proteins, such as CARDIF and STING. Our hypothesis states that these modulators of the innate immune system have an influence on liver regeneration. Methods: We use a newly established CARDIF/STING knockout mouse model and a C57BL/6 control cohort. A 2/3 partial hepatectomy (PH) was performed in both groups (n=60 mice in total). Liver regeneration was quantified by liver-to-body weight ratio, proliferation was determined by BrdU staining, RNA- and protein levels of proliferation markers were analyzed in resected tissues and pro-inflammatory cytokines were measured in murine serum. Results: CARDIF/STING knockout mice showed a significantly impaired liver regeneration after PH. Expression analysis of Interleukin-6 revealed a significant decrease in the wild type cohort after PH. In CARDIF/STING knockout mice, the proliferation marker Cyclin D1 was decreased until 24 hours after surgery, while p21Cip1 expression was increased 8h post-PH. Conclusion: Together, these data provide the first experimental evidence that CARDIF/STING knockout mice show a delayed liver regeneration. In the absence of these two proteins, we observed a modulated immune response which lead to a negative regulation of the proliferative capacity after partial hepatectomy. This finding could impact on the future development of molecular therapies making use of the innate immune system.

Suppression of YAP/TAZ-Notch1-NICD axis by bromodomain and extraterminal protein inhibition impairs liver regeneration.

Background and aims: Biological mechanisms that control liver regeneration remain poorly defined. However, these mechanisms are remarkable issues in the clinic that affect management of hepatic loss caused by liver surgery, traumatic injury, chronic infection, or liver poisoning. Increasing evidence has shown that various growth factors, cytokines, and metabolic signaling pathways affect the liver regenerative process. Our aim is to study the effect of bromodomain and extraterminal (BET) protein inhibition on liver regeneration and its mechanism.Methods: We studied the role of BET protein inhibitor, JQ1, in liver regeneration in a mouse model after 70% partial hepatectomy (PH). We evaluated yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) and Notch signaling pathways, which were affected by BET protein inhibitor in mouse hepatic tissues and primary hepatocytes in vivo and AML12 cell lines in vitro. We evaluated the relationship of YAP/TAZ and Notch signaling pathway using YAP/TAZ pathway inhibitor in liver regeneration in vivo. Moreover, we analyzed the relationship of YAP/TAZ and Notch signaling pathways via overexpression or RNA silencing of Yap in AML12 cells. Furthermore, we used Yap overexpression mouse model to examine whether it can rescue liver regeneration damage caused by inhibition of BET proteins.Results: In this study, we report that BET protein inhibitor JQ1 molecule impairs the early phase of liver regeneration in a mouse model after 70% PH. Mechanistically, YAP/TAZ and Notch1-NICD pathways were suppressed by BET protein inhibitor in mouse hepatic tissues and primary hepatocytes in vivo and mouse AML12 cell lines in vitro. By using YAP/TAZ pathway inhibitor, we confirmed that the liver regeneration and the activation of Notch pathway were impaired by the inhibition of YAP/TAZ pathway in vivo. Furthermore, the study showed that Yap knockdown by shRNA in normal mouse hepatic cell line downregulated Notch1 signal transduction, whereas Yap overexpression promoted Notch1-NICD signals. Specific overexpression of Yap in mouse liver could rescue the effect of BET protein inhibition on liver regeneration injury.Conclusion: These results revealed the crucial role of the YAP/TAZ-Notch1-NICD axis in liver regeneration. Therefore, BET protein inhibitors must be used in caution in the treatment of hepatic diseases by reason of its suppressive roles in liver regeneration.

Liver-Selective MMP-9 Inhibition in the Rat Eliminates Ischemia-Reperfusion Injury and Accelerates Liver Regeneration.

Recruitment of liver sinusoidal endothelial cell progenitor cells (sprocs) from the bone marrow by vascular endothelial growth factor-stromal cell-derived factor-1 (VEGF-sdf-1) signaling promotes recovery from injury and drives liver regeneration. Matrix metalloproteinases (MMPs) can proteolytically cleave VEGF, which might inhibit progenitor cell recruitment, but systemic matrix metalloproteinase inhibition might prevent efflux of progenitors from the bone marrow. The hypothesis for this study was that liver-selective MMP-9 inhibition would protect the hepatic VEGF-sdf-1 signaling pathway, enhance bone marrow sproc recruitment, and thereby ameliorate liver injury and accelerate liver regeneration, whereas systemic MMP inhibition would impair bone marrow sproc mobilization and therefore have less benefit or be detrimental. We found that liver-selective MMP-9 inhibition accelerated liver regeneration after partial hepatectomy by 40%, whereas systemic MMP inhibition impaired liver regeneration. Liver-selective MMP-9 inhibition largely abolished warm ischemia-reperfusion injury. In the extended hepatectomy model, liver-selective MMP-9 inhibition restored liver sinusoidal endothelial cell integrity, enhanced liver regeneration, and reduced ascites. Liver-selective MMP-9 inhibition markedly increased recruitment and engraftment of bone marrow sprocs, whereas systemic MMP inhibition impaired mobilization of bone marrow sprocs and their hepatic engraftment. Hepatic MMP-9 proteolytically cleaved VEGF after partial hepatectomy. Liver-selective MMP-9 inhibition prevented VEGF cleavage and doubled protein expression of VEGF and its downstream signaling partner sdf-1. In contrast, systemic MMP inhibition enhanced recruitment and engraftment of infused allogeneic progenitors. Conclusion: Liver-selective MMP inhibition prevents proteolytic cleavage of hepatic VEGF, which enhances recruitment and engraftment of bone marrow sprocs after liver injury. This ameliorates injury and accelerates liver regeneration. Liver-selective MMP-9 inhibition may be a therapeutic tool for liver injury that damages the vasculature, whereas systemic MMP inhibition can enhance the benefit of stem cell therapy with endothelial progenitor cells.

DAMPs and sterile inflammation in drug hepatotoxicity.

Drug hepatotoxicity is the leading cause of acute liver failure (ALF) in the developed countries. The early diagnosis and treatment are still problematic, and one important reason is the lack of reliable mechanistic biomarkers and therapeutic targets; therefore, searching for new biomarkers and therapeutic targets is urgent. Drug hepatotoxicity induces severe liver cells damage and death. Dead and damaged cells release endogenous damage-associated molecular patterns (DAMPs). Increased circulating levels of DAMPs (HMGB1, histones and DNA) can reflect the severity of drug hepatotoxicity. Elevated plasma HMGB1 concentrations can serve as early and sensitive mechanistic biomarker for clinical acetaminophen hepatotoxicity. DAMPS significantly contribute to liver injury and inhibiting the release of DAMPs ameliorates experimental hepatotoxicity. In addition, HMGB1 mediates 80% of gut bacterial translocation (BT) during acetaminophen toxicity. Gut BT triggers systemic inflammation, leading to multiple organ injury and mortality. Moreover, DAMPs can trigger and extend sterile inflammation, which contributes to early phase liver injury but improves liver regeneration at the late phase of acetaminophen overdose, because anti-inflammatory treatment reduces liver injury at early phase but impairs liver regeneration at late phase of acetaminophen toxicity, whereas pro-inflammatory therapy improves late phase liver regeneration. DAMPs are promising mechanistic biomarkers and could also be the potential therapeutic targets for drug hepatotoxicity. DAMPs-triggered sterile inflammation contributes to liver injury at early phase but improves liver regeneration at later phase of acetaminophen hepatotoxicity; therefore, anti-inflammatory therapy would be beneficial at early phase but should be avoided at the late phase of acetaminophen overdose.

The impact of steatosis on liver regeneration.

Alcoholic and non-alcoholic fatty liver diseases are the leading causes of cirrhosis in Western countries. These chronic liver diseases share common pathological features ranging from steatosis to steatohepatitis. Fatty liver is associated with primary liver graft dysfunction, a higher incidence of complications/mortality after surgery, in correlation with impaired liver regeneration. Liver regeneration is a multistep process including a priming phase under the control of cytokines followed by a growth factor receptor activation phase leading to hepatocyte proliferation. This process ends when the initial liver mass is restored. Deficiency in epidermal growth factor receptor (EGFR) liver expression, reduced expression of Wee1 and Myt1 kinases, oxidative stress and alteration in hepatocyte macroautophagy have been identified as mechanisms involved in the defective regeneration of fatty livers. Besides the mechanisms, we will also discuss in this review various treatments that have been investigated in the reversal of the regeneration defect, for example, omega-3 fatty acids, pioglitazone, fibroblast growth factor (FGF)19-based chimeric molecule or growth hormone (GH). Since dysbiosis impedes liver regeneration, targeting microbiota could also be an interesting therapeutic approach.

FXR agonist obeticholic acid induces liver growth but exacerbates biliary injury in rats with obstructive cholestasis

Cholestasis impairs liver regeneration following partial liver resection (PHx). Bile acid receptor farnesoid X-receptor (FXR) is a key mediator of liver regeneration. The effects of FXR agonist obeticholic acid (OCA) on liver (re)growth were therefore studied in cholestatic rats. Animals underwent sham surgery or reversible bile duct ligation (rBDL). PHx with concurrent internal biliary drainage was performed 7 days after rBDL. Animals were untreated or received OCA (10 mg/kg/day) per oral gavage from rBDL until sacrifice. After 7 days of OCA treatment, dry liver weight increased in the rBDL + OCA group, indicating OCA-mediated liver growth. Enhanced proliferation in the rBDL + OCA group prior to PHx concurred with a rise in Ki67-positive hepatocytes, elevated hepatic Ccnd1 and Cdc25b expression, and an induction of intestinal fibroblast growth factor 15 expression. Liver regrowth after PHx was initially stagnant in the rBDL + OCA group, possibly due to hepatomegaly prior to PHx. OCA increased hepatobiliary injury markers during BDL, which was accompanied by upregulation of the bile salt export pump. There were no differences in histological liver injury. In conclusion, OCA induces liver growth in cholestatic rats prior to PHx but exacerbates biliary injury during cholestasis, likely by forced pumping of bile acids into an obstructed biliary tree.

Differential Effects of a Glucagon-Like Peptide 1 Receptor Agonist in Non-Alcoholic Fatty Liver Disease and in Response to Hepatectomy

Non-alcoholic fatty liver disease (NAFLD) is associated with post-operative liver failure (PLF) and impaired liver regeneration. We investigated the effects of a glucagon-like peptide-1 (GLP-1) receptor agonist on NAFLD, PLF and liver regeneration in mice fed chow diet or methionine/choline-deficient diet (MCD) or high fat diet (HFD). Fc-GLP-1 decreased transaminases, reduced intrahepatic triglycerides (TG) and improved MCD-induced liver dysfuction. Macrophage/Kupffer cell-related markers were also reduced although Fc-GLP-1 increased expression of genes related to natural killer (NK), cytotoxic T lymphocytes and hepatic stellate cell (HSC) activation. After partial hepatectomy (PH), survival rates increased in mice receiving Fc-GLP-1 on chow or MCD diet. However, the benefit of Fc-GLP-1 on NASH-like features was attenuated 2 weeks post-PH and liver mass restoration was not improved. At this time-period, markers of NK cells and cytotoxic T lymphocytes were further elevated in Fc-GLP-1 treated mice. Increased HSC related gene expression in livers was observed together with decreased retinyl ester content and increased retinal and retinoic acid, reflecting HSC activation. Similar effects were found in mice fed HFD receiving Fc-GLP-1. Our results shed light on the differential effects of a long-acting GLP-1R agonist in improving NAFLD and PLF, but not enhancing liver regeneration in mice.