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Earlier data on liver development demonstrated that morphogenesis of the bile duct, portal mesenchyme and hepatic artery is interdependent, yet how this interdependency is orchestrated remains unknown. Here, using 2D and 3D imaging, we first describe how portal mesenchymal cells become organised to form hepatic arteries. Next, we examined intercellular signalling active during portal area development and found that axon guidance genes are dynamically expressed in developing bile ducts and portal mesenchyme. Using tissue-specific gene inactivation in mice, we show that the repulsive guidance molecule BMP co-receptor A (RGMA)/neogenin (NEO1) receptor/ligand pair is dispensable for portal area development, but that deficient roundabout 2 (ROBO2)/SLIT2 signalling in the portal mesenchyme causes reduced maturation of the vascular smooth muscle cells that form the tunica media of the hepatic artery. This arterial anomaly does not impact liver function in homeostatic conditions, but is associated with significant tissular damage following partial hepatectomy. In conclusion, our work identifies new players in development of the liver vasculature in health and liver regeneration.
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Orientação de Axônios , Artéria Hepática , Animais , Camundongos , Ductos Biliares , Morfogênese , Inativação GênicaRESUMO
BACKGROUND AND AIMS: Surgical resection remains the gold standard for liver tumor treatment, yet the emergence of postoperative liver failure, known as the small-for-size syndrome (SFSS), poses a significant challenge. The activation of hypoxia sensors in an SFSS liver remnant initiated early angiogenesis, improving the vascular architecture, safeguarding against liver failure, and reducing mortality. The study aimed to elucidate vascular remodeling mechanisms in SFSS and their impact on hepatocyte function and subsequent liver failure. APPROACH AND RESULTS: Mice underwent extended partial hepatectomy to induce SFSS, with a subset exposed to hypoxia immediately after surgery. Hypoxia bolstered posthepatectomy survival rates. The early proliferation of liver sinusoidal cells, coupled with recruitment of putative endothelial progenitor cells, increased vascular density, improved lobular perfusion, and limited hemorrhagic events in the regenerating liver under hypoxia. Administration of granulocyte colony-stimulating factor in hepatectomized mice mimicked the effects of hypoxia on vascular remodeling and endothelial progenitor cell recruitment but failed to rescue survival. Compared to normoxia, hypoxia favored hepatocyte function over proliferation, promoting functional preservation in the regenerating remnant. Injection of Adeno-associated virus serotype 8-thyroxine-binding globulin-hepatocyte nuclear factor 4 alpha virus for hepatocyte-specific overexpression of hepatocyte nuclear factor 4 alpha, the master regulator of hepatocyte function, enforced functionality in proliferating hepatocytes but did not rescue survival. The combination of hepatocyte nuclear factor 4 alpha overexpression and granulocyte colony-stimulating factor treatment rescued survival after SFSS-setting hepatectomy. CONCLUSIONS: In summary, SFSS arises from an imbalance and desynchronized interplay between functional regeneration and vascular restructuring. To improve survival following SFSS hepatectomy, it is essential to adopt a 2-pronged strategy aimed at preserving the function of proliferating parenchymal cells and simultaneously attenuating vascular damage.
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BACKGROUND: The RAPID (Resection And Partial Liver Transplantation with Delayed total hepatectomy) procedure involves left hepatectomy with orthotopic implantation of a left lobe and right portal vein ligation. This technique induces volumetric graft increase, allowing for a right completion hepatectomy within 15 days. Notably, there is a lack of data on the hemodynamics of Small-for-Size (SFS) grafts exposed to portal overflow without triggering SFS syndrome. METHODS: A prospective single-center protocol included eight living donors and eight RAPID non-cirrhotic recipients. Comprehensive clinical and biological data were collected, accompanied by intraoperative arterial and portal flow and pressure measurements. Early kinetic growth rate (eKGR%) and graft function were assessed using CT and 99Tc-mebrofenin scintigraphy on postoperative days 7 and 14. Findings were compared with retrospective data from13 left Living Donor Liver Transplantation (LDLT) recipients. RESULTS: The median Graft-body weight ratio was 0.41% (IQR, 0.34 to 0.49), markedly lower than in LDLT. However, there was no significant difference in eKGR between RAPID and LDLT grafts. Sequential analysis revealed variable eKGR per day: 10.6% (7.8-13.2) in the first week and 7.6% (6-9.1) in the second week post-transplantation. Indexed portal flow (iQpv) was significantly higher in RAPID compared to left LDLT (P=0.01). No hemodynamic parameters were found to correlate with regeneration speed. We modulated portal flow in 2 out of 8 cases. CONCLUSIONS: This study presents the first report of hemodynamic and volumetric data for the RAPID technique. Despite initial graft volumes falling below conventional LDLT recommendations, the study highlights acceptable clinical outcomes.
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Bile acids are signaling mediators, enabling intricate communication between tissues and the gut microbiota, and are involved in the pathophysiology of several immune and metabolic disorders. In this commentary, we discuss the importance of the gut microbiota in the Cyp2c70 knock-out mice, which are considered as a promising 'humanized' experimental resource for studying bile acids and their role in pathological conditions. We also discuss how Cyp2c70-deficient mice contribute to enhancing the translatability of preclinical studies in murine models to humans.
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Microbioma Gastrointestinal , Humanos , Animais , Camundongos , Ácidos e Sais Biliares , Camundongos Knockout , Transdução de SinaisRESUMO
Myosteatosis is highly prevalent in metabolic dysfunction-associated steatotic liver disease (MASLD) and could reciprocally impact liver function. Decreasing muscle fat could be indirectly hepatoprotective in MASLD. We conducted a review to identify interventions reducing myosteatosis and their impact on liver function. Non-pharmacological interventions included diet (caloric restriction or lipid enrichment), bariatric surgery and physical activity. Caloric restriction in humans achieving a mean weight loss of 3% only reduces muscle fat. Lipid-enriched diet increases liver fat in human with no impact on muscle fat, except sphingomyelin-enriched diet which reduces both lipid contents exclusively in pre-clinical studies. Bariatric surgery, hybrid training (resistance exercise and electric stimulation) or whole-body vibration in human decrease both liver and muscle fat. Physical activity impacts both phenotypes by reducing local and systemic inflammation, enhancing insulin sensitivity and modulating the expression of key mediators of the muscle-liver-adipose tissue axis. The combination of diet and physical activity acts synergistically in liver, muscle and white adipose tissue, and further decrease muscle and liver fat. Several pharmacological interventions (patchouli alcohol, KBP-089, 2,4-dinitrophenol methyl ether, adipoRon and atglistatin) and food supplementation (vitamin D or resveratrol) improve liver and muscle phenotypes in pre-clinical studies by increasing fatty acid oxidation and anti-inflammatory properties. These interventions are effective in reducing myosteatosis in MASLD while addressing the liver disease itself. This review supports that disturbances in inter-organ crosstalk are key pathophysiological mechanisms involved in MASLD and myosteatosis pathogenesis. Focusing on the skeletal muscle might offer new therapeutic strategies to treat MASLD by modulating the interactions between liver and muscles.
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Cirurgia Bariátrica , Humanos , Fígado/metabolismo , Restrição Calórica , Exercício Físico/fisiologia , Músculo Esquelético/metabolismo , Hepatopatia Gordurosa não Alcoólica/terapia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fígado Gorduroso/terapia , Resistência à InsulinaRESUMO
Background Body composition data have been limited to adults with disease or older age. The prognostic impact in otherwise asymptomatic adults is unclear. Purpose To use artificial intelligence-based body composition metrics from routine abdominal CT scans in asymptomatic adults to clarify the association between obesity, liver steatosis, myopenia, and myosteatosis and the risk of mortality. Materials and Methods In this retrospective single-center study, consecutive adult outpatients undergoing routine colorectal cancer screening from April 2004 to December 2016 were included. Using a U-Net algorithm, the following body composition metrics were extracted from low-dose, noncontrast, supine multidetector abdominal CT scans: total muscle area, muscle density, subcutaneous and visceral fat area, and volumetric liver density. Abnormal body composition was defined by the presence of liver steatosis, obesity, muscle fatty infiltration (myosteatosis), and/or low muscle mass (myopenia). The incidence of death and major adverse cardiovascular events were recorded during a median follow-up of 8.8 years. Multivariable analyses were performed accounting for age, sex, smoking status, myosteatosis, liver steatosis, myopenia, type 2 diabetes, obesity, visceral fat, and history of cardiovascular events. Results Overall, 8982 consecutive outpatients (mean age, 57 years ± 8 [SD]; 5008 female, 3974 male) were included. Abnormal body composition was found in 86% (434 of 507) of patients who died during follow-up. Myosteatosis was found in 278 of 507 patients (55%) who died (15.5% absolute risk at 10 years). Myosteatosis, obesity, liver steatosis, and myopenia were associated with increased mortality risk (hazard ratio [HR]: 4.33 [95% CI: 3.63, 5.16], 1.27 [95% CI: 1.06, 1.53], 1.86 [95% CI: 1.56, 2.21], and 1.75 [95% CI: 1.43, 2.14], respectively). In 8303 patients (excluding 679 patients without complete data), after multivariable adjustment, myosteatosis remained associated with increased mortality risk (HR, 1.89 [95% CI: 1.52, 2.35]; P < .001). Conclusion Artificial intelligence-based profiling of body composition from routine abdominal CT scans identified myosteatosis as a key predictor of mortality risk in asymptomatic adults. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Tong and Magudia in this issue.
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Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Fígado Gorduroso , Sarcopenia , Humanos , Masculino , Adulto , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Diabetes Mellitus Tipo 2/complicações , Inteligência Artificial , Composição Corporal , Obesidade/patologia , Doenças Cardiovasculares/complicações , Fígado Gorduroso/complicações , Tomografia Computadorizada por Raios X/métodos , Músculo Esquelético/patologia , Sarcopenia/complicaçõesRESUMO
Bile acids synthesized within the hepatocytes are transformed by gut microorganisms and reabsorbed into the portal circulation. During their enterohepatic cycling, bile acids act as signaling molecules by interacting with receptors to regulate pathways involved in many physiological processes. The bile acid pool, composed of a variety of bile acid species, has been shown to be altered in diseases, hence contributing to disease pathogenesis. Thus, understanding the changes in bile acid pool size and composition in pathological processes will help to elaborate effective pharmacological treatments. Five crucial steps along the enterohepatic cycle shape the bile acid pool size and composition, offering five possible targets for therapeutic intervention. In this review, we provide an insight on the strategies to modulate the bile acid pool, and then we discuss the potential benefits in non-alcoholic fatty liver disease.
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Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ácidos e Sais Biliares/metabolismo , Ácidos e Sais Biliares/uso terapêutico , Hepatócitos/metabolismo , Transdução de Sinais , Fígado/metabolismoRESUMO
BACKGROUND & AIMS: Studies exploring the relationship between muscle fat content and non-alcoholic fatty liver disease (NAFLD) are scarce. Herein, we aimed to evaluate the association of muscle mass and fatty infiltration with biopsy-assessed NAFLD in patients with obesity. METHODS: At inclusion (n = 184) and 12 months after a dietary intervention (n = 15) or bariatric surgery (n = 24), we evaluated NAFLD by liver biopsy, and skeletal muscle mass index (SMI) by CT (CT-SMI) or bioelectrical impedance analysis (BIA-SMI). We developed an index to evaluate absolute fat content in muscle (skeletal muscle fat index [SMFI]) from CT-based psoas muscle density (SMFIPsoas). RESULTS: Muscle mass was higher in patients with NAFLD than in those without (CT-SMI 56.8 ± 9.9 vs. 47.4 ± 6.5 cm2/m2, p <0.0001). There was no association between sarcopenia and non-alcoholic steatohepatitis (NASH). SMFIPsoas was higher in NASH ≥F2 and early NASH F0-1 than in NAFL (78.5 ± 23.6 and 73.1 ± 15.6 vs. 61.2 ± 12.6, p <0.001). A 1-point change in the score for any of the individual cardinal NASH features (i.e. steatosis, inflammation or ballooning) was associated with an increase in SMFIPsoas (all p <0.05). The association between SMFIPsoas and NASH was highly significant even after adjustment for multiple confounders (all p <0.025). After intervention (n = 39), NASH improvement, defined by NAFLD activity score <3 or a 2-point score reduction, was achieved in more than 75% of patients (n = 25 or n = 27, respectively) that had pre-established NASH at inclusion (n = 32) and was associated with a significant decrease in SMFIPsoas (p <0.001). Strikingly, all patients who had ≥11% reduction in SMFIPsoas achieved NASH improvement (14/14, p <0.05). CONCLUSIONS: Muscle fat content, but not muscle mass, is strongly and independently associated with NASH. All individuals who achieved a ≥11% decrease in SMFIPsoas after intervention improved their NASH. These data indicate that muscle fatty infiltration could be a potential marker for (and perhaps a pathophysiological contributor to) NASH. LAY SUMMARY: The fat content in skeletal muscles is highly reflective of the severity of non-alcoholic fatty liver disease (NAFLD) in patients with morbid obesity. In particular, muscle fat content is strongly associated with non-alcoholic steatohepatitis (NASH) and decreases upon NASH improvement. These data indicate that muscle fatty infiltration could be a marker and possible pathophysiological contributor to NASH.
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Tecido Adiposo/anormalidades , Hepatopatia Gordurosa não Alcoólica/etiologia , Tecido Adiposo/fisiopatologia , Adulto , Análise de Variância , Estudos de Coortes , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Músculos/anormalidades , Músculos/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Razão de ChancesRESUMO
Liver sinusoids are lined by liver sinusoidal endothelial cells (LSEC), which represent approximately 15 to 20% of the liver cells, but only 3% of the total liver volume. LSEC have unique functions, such as fluid filtration, blood vessel tone modulation, blood clotting, inflammatory cell recruitment, and metabolite and hormone trafficking. Different subtypes of liver endothelial cells are also known to control liver zonation and hepatocyte function. Here, we have reviewed the origin of LSEC, the different subtypes identified in the liver, as well as their renewal during homeostasis. The liver has the exceptional ability to regenerate from small remnants. The past decades have seen increasing awareness in the role of non-parenchymal cells in liver regeneration despite not being the most represented population. While a lot of knowledge has emerged, clarification is needed regarding the role of LSEC in sensing shear stress and on their participation in the inductive phase of regeneration by priming the hepatocytes and delivering mitogenic factors. It is also unclear if bone marrow-derived LSEC participate in the proliferative phase of liver regeneration. Similarly, data are scarce as to LSEC having a role in the termination phase of the regeneration process. Here, we review what is known about the interaction between LSEC and other liver cells during the different phases of liver regeneration. We next explain extended hepatectomy and small liver transplantation, which lead to "small for size syndrome" (SFSS), a lethal liver failure. SFSS is linked to endothelial denudation, necrosis, and lobular disturbance. Using the knowledge learned from partial hepatectomy studies on LSEC, we expose several techniques that are, or could be, used to avoid the "small for size syndrome" after extended hepatectomy or small liver transplantation.
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Células Endoteliais , Hepatectomia , Hepatócitos , Falência Hepática/patologia , Regeneração Hepática , Fígado , Animais , Células Endoteliais/citologia , Células Endoteliais/patologia , Hepatócitos/citologia , Hepatócitos/patologia , Humanos , Fígado/citologia , Fígado/patologiaRESUMO
Chronic alcohol consumption and alcohol-associated liver disease (ALD) represent a major public health problem worldwide. Only a minority of patients with an alcohol-use disorder (AUD) develop severe forms of liver disease (e.g., steatohepatitis and fibrosis) and finally progress to the more advanced stages of ALD, such as severe alcohol-associated hepatitis and decompensated cirrhosis. Emerging evidence suggests that gut barrier dysfunction is multifactorial, implicating microbiota changes, alterations in the intestinal epithelium, and immune dysfunction. This failing gut barrier ultimately allows microbial antigens, microbes, and metabolites to translocate to the liver and into systemic circulation. Subsequent activation of immune and inflammatory responses contributes to liver disease progression. Here we review the literature about the disturbance of the different host defense mechanisms linked to gut barrier dysfunction, increased microbial translocation, and impairment of liver and systemic inflammatory responses in the different stages of ALD.
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Disbiose/patologia , Microbioma Gastrointestinal , Hepatopatias Alcoólicas/complicações , Animais , Disbiose/microbiologia , Humanos , Hepatopatias Alcoólicas/microbiologiaRESUMO
OBJECTIVE: Pancreatic cancer can arise from precursor lesions called intraductal papillary mucinous neoplasms (IPMN), which are characterised by cysts containing papillae and mucus-producing cells. The high frequency of KRAS mutations in IPMN and histological analyses suggest that oncogenic KRAS drives IPMN development from pancreatic duct cells. However, induction of Kras mutation in ductal cells is not sufficient to generate IPMN, and formal proof of a ductal origin of IPMN is still missing. Here we explore whether combining oncogenic KrasG12D mutation with an additional gene mutation known to occur in human IPMN can induce IPMN from pancreatic duct cells. DESIGN: We created and phenotyped mouse models in which mutations in Kras and in the tumour suppressor gene liver kinase B1 (Lkb1/Stk11) are conditionally induced in pancreatic ducts using Cre-mediated gene recombination. We also tested the effect of ß-catenin inhibition during formation of the lesions. RESULTS: Activating KrasG12D mutation and Lkb1 inactivation synergised to induce IPMN, mainly of gastric type and with malignant potential. The mouse lesions shared several features with human IPMN. Time course analysis suggested that IPMN developed from intraductal papillae and glandular neoplasms, which both derived from the epithelium lining large pancreatic ducts. ß-catenin was required for the development of glandular neoplasms and subsequent development of the mucinous cells in IPMN. Instead, the lack of ß-catenin did not impede formation of intraductal papillae and their progression to papillary lesions in IPMN. CONCLUSION: Our work demonstrates that IPMN can result from synergy between KrasG12D mutation and inactivation of a tumour suppressor gene. The ductal epithelium can give rise to glandular neoplasms and papillary lesions, which probably both contribute to IPMN formation.
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Adenocarcinoma Mucinoso/genética , Mutação/genética , Neoplasias Intraductais Pancreáticas/genética , Neoplasias Intraductais Pancreáticas/patologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Quinases Ativadas por AMP , Adenocarcinoma Mucinoso/patologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Camundongos , Fatores de TempoRESUMO
Pathologists use a semiquantitative scoring system (NAS or SAF score) to facilitate the reporting of disease severity and evolution. Similar scores are applied for the same purposes in rodents. Histological scores have inherent inter- and intra-observer variability and yield discrete and not continuous values. Here we performed an automatic numerical quantification of NASH features on liver sections in common preclinical NAFLD/NASH models. High-fat diet-fed foz/foz mice (Foz HF) or wild-type mice (WT HF) known to develop progressive NASH or an uncomplicated steatosis, respectively, and C57Bl6 mice fed a choline-deficient high-fat diet (CDAA) to induce steatohepatitis were analyzed at various time points. Automated software image analysis of steatosis, inflammation, and fibrosis was performed on digital images from entire liver sections. Data obtained were compared with the NAS score, biochemical quantification, and gene expression. As histologically assessed, WT HF mice had normal liver up to week 34 when they harbor mild steatosis with if any, little inflammation. Foz HF mice exhibited grade 2 steatosis as early as week 4, grade 3 steatosis at week 12 up to week 34; inflammation and ballooning increased gradually with time. Automated measurement of steatosis (macrovesicular steatosis area) revealed a strong correlation with steatosis scores (r = 0.89), micro-CT liver density, liver lipid content (r = 0.89), and gene expression of CD36 (r = 0.87). Automatic assessment of the number of F4/80-immunolabelled crown-like structures strongly correlated with conventional inflammatory scores (r = 0.79). In Foz HF mice, collagen deposition, evident at week 20 and progressing at week 34, was automatically quantified on picrosirius red-stained entire liver sections. The automated procedure also faithfully captured and quantitated macrovesicular steatosis, mixed inflammation, and pericellular fibrosis in CDAA-induced steatohepatitis. In conclusion, the automatic numerical analysis represents a promising quantitative method to rapidly monitor NAFLD activity with high-throughput in large preclinical studies and for accurate monitoring of disease evolution.
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Modelos Animais de Doenças , Processamento de Imagem Assistida por Computador , Fígado/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Índice de Gravidade de Doença , Animais , Fibrose , Lipídeos/análise , Fígado/química , Fígado/patologia , Macrófagos/citologia , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/patologia , Microtomografia por Raio-XRESUMO
Ductular reaction (DR) is observed in virtually all liver diseases in both humans and rodents. Depending on the injury, DR is confined within the periportal area or invades the parenchyma. On severe hepatocellular injury, invasive DR has been proposed to arise for supplying the liver with new hepatocytes. However, experimental data evidenced that DR contribution to hepatocyte repopulation is at the most modest, unless replicative capacity of hepatocytes is abrogated. Herein, we proposed that invasive DR could contribute to operating hepatobiliary junctions on hepatocellular injury. The choline-deficient ethionine-supplemented mouse model of hepatocellular injury and human liver samples were used to evaluate the hepatobiliary junctional role of the invasive form of DR. Choline-deficient ethionine-supplemented-induced DR expanded as biliary epithelium into the lobule and established new junctions with the canaliculi. By contrast, no new ductular-canalicular junctions were observed in mouse models of biliary obstructive injury exhibiting noninvasive DR. Similarly, in humans, an increased number of hepatobiliary junctions were observed in hepatocellular diseases (viral, drug induced, or metabolic) in which DR invaded the lobule but not in biliary diseases (obstruction or cholangitis) in which DR was contained within the portal mesenchyme. In conclusion, our data in rodents and humans support that invasive DR plays a hepatobiliary junctional role to maintain structural continuity between hepatocytes and ducts in disorders affecting hepatocytes.
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Sistema Biliar/metabolismo , Hepatócitos/metabolismo , Hepatopatias/metabolismo , Fígado/lesões , Fígado/metabolismo , Animais , Sistema Biliar/patologia , Hepatócitos/patologia , Humanos , Fígado/patologia , Hepatopatias/patologia , Masculino , CamundongosRESUMO
Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) allows extended hepatectomy in patients with an extremely small future liver remnant (FLR). Current rodent models of ALPPS do not include resection resulting in insufficient-for-survival FLR, or they do incorporate liver mass reduction prior to ALPPS. Differences in FLR volume and surgical procedures could bias our understanding of physiological and hemodynamic mechanisms. We aimed to establish a rat ALPPS model with minimal FLR without prior parenchymal resection. In rodents, the left median lobe (LML) represents 10% of total liver. Partial hepatectomy (PHx) sparing LML and pericaval parenchyma represents our reference 87% resection. The first step in the procedure is either portal vein ligation (PVL) corresponding to ligation of all but the LML portal branches, or PVL with transection between the left and right median lobe segments (PVLT), and is defined as ALPPS stage-1. Second, ligated lobes were removed: PVL-PHx represents a conventional 2-stage hepatectomy, while PVLT followed by PHx is a strict reproduction of human ALPPS. In Group A, liver hypertrophy was analyzed after PVL (n = 38), PVLT (n = 47), T (n = 10), and sham (n = 10); In group B, mortality and FLR hypertrophy was assessed after PHx (n = 42), Sham-PHx (n = 6), PVL-PHx (n = 37), and PVLT-PHx (n = 45). In group A, PVLT induced rapid FLR hypertrophy compared to PVL (p < 0,05). Hepatocyte proliferation was higher in PVLT remnants (p < 0,05). In group B, PHx had a 5-day mortality rate of 84%. Sham operation prior to PHx did not improve survival (p = 0.23). In both groups, major fatalities occurred within 48 h after resection. PVL or PVLT prior to PHx reduced mortality to 33.3% (p = 0,007) or 25% (p = 0.0002) respectively, with no difference between the 2 two-stage procedures (p = 0.6). 7-day FLR hypertrophy was higher after the PVLT-PHx compared to PVL-PHx and PHx (p = 0.024). Our model reproduces human ALPPS with FLR that is insufficient for survival without liver resection prior to the stage-1 procedure. It offers an appropriate model for analyzing the mechanisms driving survival rescue and increased hypertrophy.
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Modelos Animais de Doenças , Hepatectomia/métodos , Neoplasias Hepáticas/cirurgia , Regeneração Hepática , Fígado/cirurgia , Veia Porta/cirurgia , Animais , Proliferação de Células , Hepatectomia/mortalidade , Humanos , Estimativa de Kaplan-Meier , Ligadura , Fígado/irrigação sanguínea , Fígado/fisiopatologia , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Masculino , Ratos Wistar , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Nonalcoholic steatohepatitis (NASH) is the form of nonalcoholic fatty liver disease that can evolve into cirrhosis. Lifestyle modifications achieving 10% weight loss reverse NASH, but there are no effective approved drug treatments. We previously identified defective adaptive thermogenesis as a factor contributing to metabolic syndrome and hepatic steatosis. We have now tested whether increasing nonshivering thermogenesis can improve preexisting NASH in mice. In high-fat diet-fed foz/foz mice with established NASH, treatment with ß3AR agonist restored brown adipose tissue (BAT) function, decreased body weight, improved glucose tolerance, and reduced hepatic lipid content compared to untreated counterparts, but had no impact on liver inflammation or on nonalcoholic fatty liver disease activity score (NAS). Similarly, ß3AR agonist did not alter liver pathology in other steatohepatitis models, including MCD diet-fed diabetic obese db/db mice. Caloric restriction alone alleviated the hepatic inflammatory signature in foz/foz mice. Addition of a ß3AR agonist to mice subjected to caloric restriction enhanced weight loss and glucose tolerance, and improved liver steatosis, hepatocellular injury, and further reduced liver inflammation. These changes contributed to a significantly lower NAS score such as no (0/9) animals in this group fulfilled the criteria for NASH pathology compared to eight out of ten mice under caloric restriction alone. In conclusion, ß3AR agonist counteracts features of the metabolic syndrome and alleviates steatosis, but does not reverse NASH. However, when coupled with weight loss therapy, BAT stimulation provides additional therapeutic advantages and reverses NASH.
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Acetanilidas/uso terapêutico , Tecido Adiposo Marrom/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Dioxóis/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Tiazóis/uso terapêutico , Acetanilidas/farmacologia , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Restrição Calórica , Dieta Hiperlipídica/efeitos adversos , Dioxóis/farmacologia , Avaliação Pré-Clínica de Medicamentos , Fígado/efeitos dos fármacos , Síndrome Metabólica/tratamento farmacológico , Camundongos , Hepatopatia Gordurosa não Alcoólica/dietoterapia , Hepatopatia Gordurosa não Alcoólica/etiologia , Tiazóis/farmacologiaRESUMO
Portal hyperperfusion and "dearterialization" of the liver remnant are the main pathogenic mechanisms for Small For Size syndrome (SFSS). Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) induces rapid remnant hypertrophy. We hypothesized a similar increase in portal pressure/flow into the future liver remnant in ALPPS and SFSS-setting hepatectomies. In a rodent model, ALPPS was compared to SFSS-setting hepatectomy. We assessed mortality, remnant hypertrophy, hepatocyte proliferation, portal and hepatic artery flow, hypoxia-induced response, and liver sinusoidal morphology. SFSS-hepatectomy rats were subjected to local (hepatic artery ligation) or systemic (Dimethyloxalylglycine) hypoxia. ALLPS prevented mortality in SFSS-setting hepatectomies. Portal hyperperfusion per liver mass was similar in ALLPS and SFSS. Compared to SFSS, efficient arterial perfusion of the remnant was significantly lower in ALPPS causing pronounced hypoxia confirmed by pimonidazole immunostaining, activation of hypoxia sensors and upregulation of neo-angiogenic genes. Liver sinusoids, larger in ALPPS, collapsed in SFSS. Induction of hypoxia in SFSS reduced mortality. Hypoxia had no impact on hepatocyte proliferation but contributed to the integrity of sinusoidal morphology. ALPPS hemodynamically differ from SFSS by a much lower arterial flow in ALPPS's FLR. We show that the ensuing hypoxic response is essential for the function of the regenerating liver by preserving sinusoidal morphology.
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Hepatectomia/efeitos adversos , Hipertrofia/etiologia , Hipóxia , Regeneração Hepática , Veia Porta/cirurgia , Complicações Pós-Operatórias/etiologia , Animais , Hipertrofia/patologia , Masculino , Complicações Pós-Operatórias/patologia , Ratos , Ratos Wistar , SíndromeRESUMO
Skeletal muscle is a tissue that represents 30-40% of total body mass in healthy humans and contains up to 75% of total body proteins. It is thus the largest organ in non-obese subjects. The past few years have seen increasing awareness of the prognostic value of appreciating changes in skeletal muscle compartment in various chronic diseases. Hence, a low muscle mass, a low muscle function and muscle fatty infiltration are linked with poor outcomes in many pathological conditions. In particular, an affluent body of evidence links the severity, the complications and mortality of chronic liver disease (CLD) with skeletal muscle depletion. Yet it is still not clear whether low muscle mass is a cause, an aggravating factor, a consequence of the ongoing disease, or an epiphenomenon reflecting general alteration in the critically ill patient. The mechanisms by which the muscle compartment influences disease prognosis are still largely unknown. In addition, whether muscle alterations contribute to liver disease progression is an unanswered question. Here, we first review basic knowledge about muscle compartment to draw a conceptual framework for interpreting skeletal muscle alteration in CLD. We next describe recent literature on muscle wasting in cirrhosis and liver transplantation. We then discuss the implication of skeletal muscle compartment in non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), focusing on plausible metabolic disruption in muscle compartment that might participate in NAFLD progression. Finally, we discuss shortcomings and challenges we need to address in the near future prior to designate the muscle compartment as a therapeutic target in CLD.
Assuntos
Hepatopatias/fisiopatologia , Músculo Esquelético/fisiopatologia , Animais , Progressão da Doença , Humanos , Hepatopatias/patologia , Hepatopatias/psicologia , Músculo Esquelético/crescimento & desenvolvimento , Músculo Esquelético/patologiaRESUMO
Ninety percent of hepatocarcinoma (HCC) develops in a chronically damaged liver. Interactions between non-tumor stromal components, especially macrophages, and cancer cells are still incompletely understood. Our aim was to determine whether a chronically injured liver represents a favorable environment for the seeding and growth of HCC cells, and to evaluate the potential roles of macrophages infiltrated within the tumor. HCC cells were injected into the liver in healthy mice (healthy liver group [HL]) and in mice chronically treated with carbon tetrachloride (CCl4 ) for 7 weeks (CCl4 7w group). Livers were examined for the presence of tumor 2 weeks post-injection. Tumor and non-tumor tissues were analyzed for macrophage infiltration, origin (monocytes-derived vs resident macrophages) and polarization state, and MMP production. Fifty-three percent of mice developed neoplastic lesion in the HL group whereas a tumor lesion was found in all livers in the CCl4 7w group. Macrophages infiltrated more deeply the tumors of the CCl4 7w group. Evaluation of factors involved in the recruitment of macrophages and of markers of their polarization state was in favor of prominent infiltration of M2 pro-tumor monocyte-derived macrophages inside the tumors developing in a chronically injured liver. MMP-2 and -9 production, attributed to M2 pro-tumor macrophages, was significantly higher in the tumors of the CCl4 7w group. In our model, chronic liver damage promotes cancer development. Our results suggest that an injured background favors the infiltration of M2 pro-tumor monocyte-derived macrophages. These secrete MMP-2 and MMP-9 that promote tumor progression.
Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Fígado/lesões , Fígado/patologia , Animais , Tetracloreto de Carbono/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Non-alcoholic steatohepatitis (NASH) is strongly associated with overnutrition, insulin resistance, and predisposition to type 2 diabetes. To critically analyze the translational significance of currently used animal models of NASH, we reviewed articles published during the last 3 years that studied NASH pathogenesis using mouse models. Among 146 articles, 34 (23%) used models in which overnutrition was reported, and 36 (25%) demonstrated insulin resistance, with or without glucose intolerance. Half the articles contained no information on whether mice exhibited overnutrition or insulin resistance. While 75 papers (52%) reported > 2-fold increase of serum/plasma alanine aminotransferase (ALT) compared with controls, ALT levels were near normal or not reported in 48%. Liver pathology was assessed by a pathologist with an interest in liver pathology in 53% of articles published in gastroenterology/hepatology journals, versus 43-44% in other journals. While there appears to be a trend to use models that are potentially relevant to the pathogenesis of human NASH, journals currently publish data on mouse models in which overnutrition and insulin resistance do not occur, without ALT increase or appropriate analysis of NASH pathology. We recommend that investigators, reviewers, and journal editors carefully consider the validity of NASH models in current use and that moves are made to reach a consensus on what the minimal criteria should be.
Assuntos
Modelos Animais de Doenças , Hepatopatia Gordurosa não Alcoólica , Alanina Transaminase/sangue , Animais , Diabetes Mellitus Tipo 2/etiologia , Suscetibilidade a Doenças/etiologia , Humanos , Resistência à Insulina , Fígado/patologia , Camundongos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Hipernutrição/complicaçõesRESUMO
Liver regeneration is crucial for the maintenance of liver functional mass during homeostasis and diseases. In a disease context-dependent manner, liver regeneration is contributed to by hepatocytes or progenitor cells. As long as they are replicatively competent, hepatocytes are the main cell type responsible for supporting liver size homeostasisand regeneration. The concept that all hepatocytes within the lobule have the same proliferative capacity but are differentially recruited according to the localization of the wound, or whether a yet to be defined sub-population of hepatocytes supports regeneration is still debated. In a chronically or severely injured liver, hepatocytes may enter a state of replicative senescence. In such conditions, small biliary cells activate and expand, a process called ductular reaction (DR). Work in the last few decades has demonstrated that DR cells can differentiate into hepatocytes and thereby contribute to parenchymal reconstitution. In this study we will review the molecular mechanisms supporting these two processes to determine potential targets that would be amenable for therapeutic manipulation to enhance liver regeneration.