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1.
Hepatol Res ; 54(3): 272-283, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37921697

RESUMO

AIM: Following the coronavirus disease outbreak, a state of public emergency was declared worldwide, which enforced lifestyle changes. This study therefore aimed to investigate the changes in lifestyle, body composition, hepatic steatosis, and fibrosis in patients with chronic liver disease (CLD) under lockdown. METHODS: During the lockdown period, 1344 patients with CLD answered a lifestyle questionnaire. In 298 patients, body composition and liver stiffness measure (LSM)/controlled attenuation parameter (CAP) were analyzed by InBody and FibroScan, respectively, and serial data were obtained in 137 patients. RESULTS: More than half of the CLD patients answered decreases in physical activity and frequency of outings during lockdown, while diet was less affected. Overall, 58% of patients showed elevations in CAP values, which were not different statistically over time. Women, but not men, were more likely to increase CAP values during lockdown. Neither LSM nor serum fibrosis markers were elevated chronologically during lockdown. In men, body mass index (BMI), body fat percentage, and visceral fat area (VFA) were significantly increased, whereas in women, lower-limb muscle mass was significantly decreased. Patients with decreased SMI showed elevations in CAP and VFA values, and patients who exercised less showed increases in BMI. CONCLUSION: In response to lockdown, men tended to increase body fat but the degree of hepatic steatosis was less affected, while women were more likely to exacerbate hepatic steatosis with skeletal muscle loss among CLD patients. Gender-specific approaches need to be established for management of CLD patients to avoid exacerbation or comorbidity of steatotic liver disease.

2.
J Clin Med ; 12(7)2023 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-37048744

RESUMO

This study investigated the impact of partial splenic embolization (PSE) on portal hypertensive gastropathy (PHG). We retrospectively analyzed endoscopic findings and the portal venous system of 31 cirrhotic patients with PHG. The improved group was defined as the amelioration of PHG findings using the McCormack classification. Child-Pugh scores of the improved group (18 of 31 patients) were significantly lower compared with those of the non-improved group (p = 0.018). The changes in the diameters of the portal trunk and those of the spleno-portal junction and spleen hilum in the splenic vein of the improved group were significantly larger than those of the non-improved group (p = 0.007, p = 0.025, and p = 0.003, respectively). The changes in the diameters of the portal vein and splenic hilum of the splenic vein showed significant correlations with Child-Pugh score (r = 0.386, p = 0.039; r = 0.510, p = 0.004). In a multivariate analysis of baseline factors related to the improved group, Child-Pugh grade A was significantly associated with the improvement of PHG (odds ratio 6.875, p = 0.033). PSE could be useful for PHG, especially in patients with Child-Pugh grade A, at least in the short term.

3.
Hepatol Int ; 16(2): 348-358, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35060066

RESUMO

BACKGROUND: The prevalence of nonalcoholic fatty liver disease (NAFLD) and alcohol-associated/related liver disease (ALD) with metabolic syndrome is increasing globally. Metabolic syndrome and excessive alcohol consumption synergically exacerbate liver pathologies; therefore, drinking-specific serum markers unaffected by liver injury or metabolic syndrome are essential for assessing alcohol consumption. We evaluated the ratio of carbohydrate-deficient transferrin to total transferrin (%CDT) in patients with fatty liver disease, particularly focusing on its correlation with metabolic factors (UMIN000033550). METHODS: A total of 120 patients with fatty liver disease, including ALD and NAFLD, were screened for alcohol misuse using the Alcohol Use Disorders Identification Test. Associations of metabolic syndrome-related factors and hepatic steatosis/liver stiffness with drinking markers, such as %CDT, gamma-glutamyl transferase (GGT), and mean corpuscular volume (MCV), were assessed using multiple linear regression analyses. RESULTS: %CDT significantly increased with 3-4 drinks/day. The optimal cutoff value for identifying non- to light drinkers was 1.78% (sensitivity, 71.8%; specificity, 83.7%; and area under the receiver operating characteristic curve [AUROC], 0.851), which was significantly higher than that for GGT. The cutoff value for identifying heavy drinkers was 2.08% (sensitivity, 65.5%; specificity, 86.8%; and AUROC, 0.815). Multiple regression analysis revealed that this proportion was negatively correlated with body mass index, whereas GGT and MCV were influenced by multiple factors involved in liver injury and dyslipidemia. CONCLUSIONS: %CDT showed a strong correlation with alcohol consumption, independent of liver damage, steatosis/stiffness, or metabolic syndrome-related factors, indicating that it is a useful drinking marker for the accurate diagnosis of NAFLD and ALD.


Assuntos
Alcoolismo , Síndrome Metabólica , Hepatopatia Gordurosa não Alcoólica , Consumo de Bebidas Alcoólicas/efeitos adversos , Biomarcadores , Humanos , Síndrome Metabólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Transferrina/análogos & derivados , Transferrina/análise , gama-Glutamiltransferase
4.
J Pharmacol Sci ; 139(4): 373-376, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30857764

RESUMO

To investigate the relationship between the exposure and efficacy of tolvaptan, we measured pharmacokinetics of total drug at 7 days after repeated doses of 3.75 mg/day tolvaptan in 16 patients with hepatic edema. Nine patients (56.3%) were responders, which were defined as those with body weight reduction of >1.5 kg/week. Serum albumin levels were significantly lower in responders than in non-responders (P = 0.031). However, the pharmacokinetics varied greatly among individuals and was not relevant to the clinical response.


Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacocinética , Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Ascite/tratamento farmacológico , Ascite/metabolismo , Edema/tratamento farmacológico , Edema/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Hepatopatias/tratamento farmacológico , Hepatopatias/metabolismo , Tolvaptan/farmacocinética , Tolvaptan/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antagonistas dos Receptores de Hormônios Antidiuréticos/sangue , Ascite/complicações , Edema/complicações , Feminino , Humanos , Cirrose Hepática/complicações , Hepatopatias/complicações , Masculino , Pessoa de Meia-Idade , Albumina Sérica/metabolismo , Tolvaptan/sangue , Resultado do Tratamento
5.
PLoS One ; 13(4): e0196747, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29709031

RESUMO

BACKGROUND: Paritaprevir inhibits organic anion-transporting polypeptide (OATP)1B1 and OATP1B3, which transport bilirubin. Hyperbilirubinemia is an adverse event reported during hepatitis C treatment. Gadoxetic acid is also transported by OATP1B1/1B3. We evaluated whether the enhancement effect in gadoxetic acid-enhanced magnetic resonance (MR) imaging could predict the plasma concentration of paritaprevir and might anticipate the development of hyperbilirubinemia. METHODS: This prospective study evaluated 27 patients with hepatitis C who underwent gadoxetic acid-enhanced MR imaging prior to treatment with ombitasvir, paritaprevir, and ritonavir. The contrast enhancement index (CEI), a measure of liver enhancement during the hepatobiliary phase, was assessed. Plasma trough concentrations, and concentrations at 2, 4, and 6 h after dosing were determined 7 d after the start of treatment. RESULTS: Seven patients (26%) developed hyperbilirubinemia (≥ 1.6 mg/dl). Paritaprevir trough concentration (Ctrough) was significantly higher in patients with hyperbilirubinemia than in those without (p = 0.022). We found an inverse relationship between CEI and Ctrough (r = 0.612, p = 0.001), while there was not a significantly weak inverse relationship between AUC0-6 h and CEI (r = -0.338, p = 0.085). The partial correlation coefficient between CEI and Ctrough was -0.425 (p = 0.034), while excluding the effects of albumin and the FIB-4 index. Receiver operating characteristic (ROC) curve analysis showed that the CEI was relatively accurate in predicting hyperbilirubinemia, with area under the ROC of 0.882. Multivariate analysis showed that the CEI < 1.61 was the only independent predictor related to the development of hyperbilirubinemia, with an odds ratio of 9.08 (95% confidence interval 1.05-78.86, p = 0.046). CONCLUSIONS: Hepatic enhancement with gadoxetic acid was independently related to paritaprevir concentration and was an independent pretreatment factor in predicting hyperbilirubinemia. Gadoxetic acid-enhanced MR imaging can therefore be useful in determining the risk of paritaprevir-induced hyperbilirubinemia.


Assuntos
Gadolínio DTPA/química , Hepatite C/diagnóstico por imagem , Hepatite C/tratamento farmacológico , Hiperbilirrubinemia/induzido quimicamente , Compostos Macrocíclicos/efeitos adversos , Imageamento por Ressonância Magnética , Adulto , Idoso , Idoso de 80 Anos ou mais , Meios de Contraste , Ciclopropanos , Feminino , Hepatite C/complicações , Humanos , Lactamas Macrocíclicas , Masculino , Pessoa de Meia-Idade , Prolina/análogos & derivados , Estudos Prospectivos , Sulfonamidas , Fatores de Tempo , Resultado do Tratamento
6.
Hepatol Res ; 47(12): 1235-1240, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28019069

RESUMO

AIM: The indocyanine green (ICG) finger-piece method (FPM), which allows measurement of the ICG concentration by mounting a light sensor onto a finger, is used to assess liver function. We compared the ICG FPM with the conventional ICG blood sampling method (BSM) in patients with liver disorders. METHODS: Ninety consecutive patients simultaneously underwent the ICG BSM and ICG FPM. After ICG administration, blood samples were collected at 5, 10, and 15 min for the ICG BSM. The ICG concentration was measured through the finger piece by an ICG clearance meter. RESULTS: Seventy-one patients (78.9%) had Child-Pugh class A liver disease, and 19 (21.1%) had class B or C. The FPM-measured ICG plasma disappearance rate was positively correlated with the BSM-measured values (r = 0.886, P < 0.001). Bland-Altman analysis showed good agreement between the two methods (mean difference, 0.012 ± 0.018). The FPM-measured ICG plasma disappearance rate was positively correlated with the BSM-measured values both in patients with Child-Pugh class A liver disease (r = 0.821, P < 0.001) and class B or C liver disease (r = 0.859, P < 0.001). CONCLUSION: The ICG FPM may be an alternative to the ICG BSM for liver function assessment.

7.
J Clin Pharmacol ; 57(3): 369-375, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27530761

RESUMO

Simeprevir is a substrate for organic anion-transporting polypeptides (OATPs) that transport bilirubin. Hyperbilirubinemia is an adverse event reported during treatment of chronic hepatitis C patients with simeprevir plus pegylated interferon and ribavirin. Because gadoxetic acid is also a substrate of OATPs, pretreatment gadoxetic acid-enhanced magnetic resonance imaging (MRI) may predict hyperbilirubinemia during treatment. This prospective study therefore evaluated 11 consecutive patients with chronic hepatitis C who underwent gadoxetic acid-enhanced MRI prior to treatment with simeprevir plus pegylated interferon and ribavirin for 12 weeks, followed by pegylated interferon and ribavirin for an additional 12 weeks. Their contrast enhancement index (CEI), an index of liver parenchymal enhancement during the hepatobiliary phase, was assessed before treatment. Plasma trough concentrations (Ctrough ) of simeprevir were determined 7 days after its administration, and serum bilirubin concentrations were measured throughout the course of treatment. Six patients (55%) developed hyperbilirubinemia (≥1.6 mg/dL) during treatment. Ctrough was significantly higher in patients with than without hyperbilirubinemia (P = .009), with a strong inverse relationship between CEI and Ctrough (r = -0.911, P < .001). CEI was significantly lower in patients with than without hyperbilirubinemia (P = .009), but there were no significant differences between the 2 groups in pretreatment serum albumin concentrations and FIB-4 index, an index of liver fibrosis. Hepatic enhancement with gadoxetic acid was related to Ctrough of simeprevir. Gadoxetic acid-enhanced magnetic resonance imaging may predict the development of hyperbilirubinemia during treatment of hepatitis C patients with simeprevir plus pegylated interferon and ribavirin.


Assuntos
Antivirais/efeitos adversos , Meios de Contraste/administração & dosagem , Gadolínio DTPA/administração & dosagem , Hiperbilirrubinemia/induzido quimicamente , Simeprevir/efeitos adversos , Adulto , Idoso , Antivirais/uso terapêutico , Bilirrubina/sangue , Quimioterapia Combinada , Feminino , Genótipo , Hepatite C Crônica/diagnóstico por imagem , Hepatite C Crônica/tratamento farmacológico , Humanos , Hiperbilirrubinemia/diagnóstico , Interferon-alfa/uso terapêutico , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Valor Preditivo dos Testes , Estudos Prospectivos , Ribavirina/uso terapêutico , Albumina Sérica , Simeprevir/uso terapêutico
8.
Lab Invest ; 95(10): 1145-56, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26146960

RESUMO

Hepatocellular carcinoma (HCC) carries a poor prognosis with no effective treatment available other than liver transplantation for selected patients. Vascular invasion of HCC is one of the most important negative predictor of survival. As the regulation of invasion of HCC cells is not well understood, our aim was to study the mechanisms by which galectin 3, a ß-galactosidase-binding lectin mediates HCC cell migration. HCC was induced by N-diethylnitrosamine in wild-type and galectin 3(-/-) mice, and tumor formation, histology, and tumor cell invasion were assessed. The galectin 3(-/-) mice developed significantly smaller tumor burden with a less invasive phenotype than the wild-type animals. Galectin 3 was upregulated in the wild-type HCC tumor tissue, but not in the surrounding parenchyma. Galectin 3 expression in HCC was induced by NF-κB transactivation as determined by chromatin immunoprecipitation assays. In vitro studies assessed the pro-migratory effects of galectin 3. The migration of hepatoma cells was significantly decreased after transfection by the galectin 3 siRNA and also after using the Rho kinase inhibitor Y-27632. The reorganization of the actin cytoskeleton, RhoA GTPase activity and the phosphorylation of MLC2 (myosin light chain 2) were decreased in the galectin 3 siRNA-transfected cells. In addition, in vitro and in vivo evidence showed that galectin 3 deficiency reduced hepatoma cell proliferation and increased their apoptosis rate. In conclusion, galectin 3 is an important lectin that is induced in HCC cells, and promotes hepatoma cell motility and invasion by an autocrine pathway. Targeting galectin 3 therefore could be an important novel treatment strategy to halt disease progression.


Assuntos
Carcinoma Hepatocelular/metabolismo , Galectina 3/metabolismo , Neoplasias Hepáticas/metabolismo , Fígado/metabolismo , Quinase de Cadeia Leve de Miosina/metabolismo , Proteínas de Neoplasias/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/metabolismo , Citoesqueleto de Actina/patologia , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Miosinas Cardíacas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Galectina 3/antagonistas & inibidores , Galectina 3/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Cadeias Leves de Miosina/metabolismo , Quinase de Cadeia Leve de Miosina/antagonistas & inibidores , Quinase de Cadeia Leve de Miosina/química , Invasividade Neoplásica , Proteínas de Neoplasias/agonistas , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/agonistas , Proteína rhoA de Ligação ao GTP/antagonistas & inibidores , Proteína rhoA de Ligação ao GTP/genética
9.
Hepatology ; 58(4): 1339-48, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23703665

RESUMO

UNLABELLED: Advanced glycation endproducts (AGEs) accumulate in patients with diabetes, yet the link between AGEs and inflammatory and fibrogenic activity in nonalcoholic steatohepatitis (NASH) has not been explored. Tumor necrosis factor alpha (TNF-α)-converting enzyme (TACE) is at the center of inflammatory processes. Because the main natural regulator of TACE activity is the tissue inhibitor of metalloproteinase 3 (Timp3), we hypothesized that AGEs induce TACE through nicotinamide adenine dinucleotide phosphate reduced oxidase 2 (NOX2); and the down-regulation of Sirtuin 1 (Sirt1)/Timp3 pathways mediate fibrogenic activity in NASH. The role of NOX2, Sirt1, Timp3, and TACE was evaluated in choline-deficient L-amino acid defined (CDAA) or Western diet (WD)-fed wild-type (WT) and NOX2(-/-) mice. To restore Timp3, mice were injected with adenovirus (Ad)-Timp3. Sirt1 and Timp3 expressions were studied in livers from NASH patients, and we found that their levels were significantly lower than in healthy controls. In WT mice on the CDAA or WD, Sirt1 and Timp3 expressions were lower, whereas production of reactive oxidative species and TACE activity significantly increased with an increase in active TNF-α production as well as induction of fibrogenic transcripts. Ad-Timp3 injection resulted in a significant decline in TACE activity, procollagen α1 (I), alpha smooth muscle actin (α-SMA) and transforming growth factor beta (TGF-ß) expression. NOX2(-/-) mice on the CDAA or WD had no significant change in Sirt1, Timp3, and TACE activity or the fibrosis markers assessed. In vitro, AGE exposure decreased Sirt1 and Timp3 in hepatic stellate cells by a NOX2-dependent pathway, and TACE was induced after exposure to AGEs. CONCLUSION: TACE activation is central to the pathogenesis of NASH and is mediated by AGEs through NOX2 induction and down-regulation of Sirt1/Timp3 pathways.


Assuntos
Proteínas ADAM/metabolismo , Fígado Gorduroso/complicações , Fígado Gorduroso/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Proteína ADAM17 , Actinas/metabolismo , Animais , Estudos de Casos e Controles , Células Cultivadas , Modelos Animais de Doenças , Produtos Finais de Glicação Avançada/farmacologia , Humanos , Técnicas In Vitro , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidase 2 , NADPH Oxidases/deficiência , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Hepatopatia Gordurosa não Alcoólica , Ratos Sprague-Dawley , Transdução de Sinais/imunologia , Sirtuína 1/metabolismo , Inibidor Tecidual de Metaloproteinase-3/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
10.
Hepatol Res ; 42(11): 1112-8, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22583683

RESUMO

AIM: Recent evidence suggests that protein degradation system autophagy is implicated in a component of innate immunity. We report here that suppression of autophagy in Kupffer cells due to hepatic steatosis enhances an inflammatory response to endotoxin. METHODS: Kupffer cells were isolated from C57BL/6J mice fed chow diet (control) or high-fat diet (HFD) for 12 weeks, liver-specific autophagy-deficient mice (Atg7(F/F) :Mx1-Cre) and wild-type mice (Atg7(F/F) ). Kupffer cells were incubated with 100 ng/mL lipopolysaccharide (LPS). The concentration of tumor necrosis factor (TNF)-α in media was measured by enzyme-linked immunoassay. Expression of Toll-like receptor (TLR)4, IκB kinase (IKK)-α/ß, p38, p62 and LC3 in Kupffer cells was evaluated by western blot analysis. RESULTS: Incubation with LPS increased LC3-II expression of Kupffer cells from control mice; however, an increase in LC3-II expression due to LPS was suppressed in Kupffer cells from HFD mice. Moreover, both p62 expression and TNF-α production in Kupffer cells from HFD mice was higher than control mice. On the other hand, LPS exposure increased TNF-α production from autophagy-deficient Kupffer cells more than wild type. There was no significant difference in expression of TLR4 between wild and autophagy-deficient Kupffer cells. Nevertheless, activation of p38 or IKK in Kupffer cells due to LPS was augmented by autophagy deficiency. The addition of the p38 inhibitor SB203580 attenuated TNF-α production in both wild and autophagy-deficient Kupffer cells. CONCLUSION: These results suggest that suppression of autophagy observed in Kupffer cells from steatotic liver sensitizes to endotoxin. In conclusion, suppression of autophagy may play a pivotal role on progression of NAFLD.

11.
J Gastroenterol ; 47(4): 433-43, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22124574

RESUMO

BACKGROUND: Previous reports indicate that mitochondrial dysfunction is essential for the development of liver injury due to acetaminophen. On the other hand, autophagy, which is a major catabolic pathway, plays a critical role in removing protein aggregates, as well as damaged or excess mitochondria in order to maintain intracellular homeostasis. The aim of this study was to clarify if autophagy is linked to liver injury due to acetaminophen. METHODS: Acetaminophen was administered intraperitoneally to liver-specific Atg7-deficient mice and wild-type mice. A variety of cellular and molecular approaches were used to evaluate the role of autophagy in acetaminophen-induced cell death. RESULTS: Treatment with acetaminophen induced formation of autophagosomes in hepatocytes from wild-type mice, but not in Atg7-deficient mice. Autophagy deficiency enhanced acetaminophen-induced liver injury and activation of caspase-3 and -7 in the liver. Acetaminophen-induced reactive oxygen species (ROS) production, mitochondrial membrane depolarization, and JNK activation in hepatocytes were accelerated by autophagy deficiency. The combination of cyclosporin A or JNK inhibitor (SP600125) with acetaminophen blunted both acetaminophen-induced apoptotic and necrotic cell death in autophagy-deficient hepatocytes. CONCLUSIONS: Induction of autophagy during acetaminophen treatment plays a pivotal role in the protection against acetaminophen-induced hepatotoxicity through the removal of damaged mitochondria and oxidative stress.


Assuntos
Acetaminofen/toxicidade , Autofagia/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Fígado/efeitos dos fármacos , Mitocôndrias/metabolismo , Acetaminofen/efeitos adversos , Acetaminofen/farmacologia , Animais , Apoptose , Proteína 7 Relacionada à Autofagia , Técnicas de Cultura de Células , Citometria de Fluxo , Immunoblotting , Fígado/fisiopatologia , Potencial da Membrana Mitocondrial , Camundongos , Camundongos Knockout , Microscopia Eletrônica , Proteínas Associadas aos Microtúbulos/deficiência , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
12.
Am J Physiol Gastrointest Liver Physiol ; 302(4): G439-46, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22159281

RESUMO

Hepatic stellate cells (HSC), the key fibrogenic cells of the liver, transdifferentiate into myofibroblasts upon phagocytosis of apoptotic hepatocytes. Galectin-3, a ß-galactoside-binding lectin, is a regulator of the phagocytic process. In this study, our aim was to study the mechanism by which extracellular galectin-3 modulates HSC phagocytosis and activation. The role of galectin-3 in engulfment was evaluated by phagocytosis and integrin binding assays in primary HSC. Galectin-3 expression was studied by real-time PCR and enzyme-linked immunosorbent assay, and in vivo studies were done in wild-type and galectin-3(-/-) mice. We found that HSC from galectin-3(-/-) mice displayed decreased phagocytic activity, expression of transforming growth factor-ß1, and procollagen α1(I). Recombinant galectin-3 reversed this defect, suggesting that extracellular galectin-3 is required for HSC activation. Galectin-3 facilitated the α(v)ß(3) heterodimer-dependent binding, indicating that galectin-3 modulates HSC phagocytosis via cross-linking this integrin and enhancing the tethering of apoptotic cells. Blocking integrin α(v)ß(3) resulted in decreased phagocytosis. Galectin-3 expression and release were induced in active HSC engulfing apoptotic cells, and this was mediated by the nuclear factor-κB signaling. The upregulation of galectin-3 in active HSC was further confirmed in vivo in bile duct-ligated (BDL) rats. Galectin-3(-/-) mice displayed significantly decreased fibrosis, with reduced expression of α-smooth muscle actin and procollagen α1(I) following BDL. In summary, extracellular galectin-3 plays a key role in liver fibrosis by mediating HSC phagocytosis, activation, and subsequent autocrine and paracrine signaling by a feedforward mechanism.


Assuntos
Galectina 3/metabolismo , Células Estreladas do Fígado/metabolismo , Cirrose Hepática/metabolismo , Fígado/metabolismo , Fagocitose/fisiologia , Animais , Adesão Celular/fisiologia , Diferenciação Celular/fisiologia , Galectina 3/genética , Células Estreladas do Fígado/patologia , Fígado/patologia , Cirrose Hepática/genética , Cirrose Hepática/patologia , Camundongos , Camundongos Knockout , NF-kappa B/genética , NF-kappa B/metabolismo , Transdução de Sinais/genética
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