RESUMO
BACKGROUND: We investigated the effects of ketamine on desaturation and the risk of nursing home discharge in patients undergoing procedural sedation by anaesthetists. METHODS: We included adult patients who underwent procedures under monitored anaesthetic care between 2005 and 2021 at two academic healthcare networks in the USA. The primary outcome was intraprocedural oxygen desaturation, defined as oxygen saturation <90% for ≥2 consecutive minutes. The co-primary outcome was a nursing home discharge. RESULTS: Among 234,170 included patients undergoing procedural sedation, intraprocedural desaturation occurred in 5.6% of patients who received ketamine vs 5.2% of patients who did not receive ketamine (adjusted odds ratio [ORadj] 1.22, 95% confidence interval [CI] 1.15-1.29, P<0.001; adjusted absolute risk difference [ARDadj] 1%, 95% CI 0.7-1.3%, P<0.001). The effect was magnified by age >65 yr, smoking, or preprocedural ICU admission (P-for-interaction <0.001, ORadj 1.35, 95% CI 1.25-1.45, P<0.001; ARDadj 2%, 95% CI 1.56-2.49%, P<0.001), procedural risk factors (upper endoscopy of longer than 2 h; P-for-interaction <0.001, ORadj 2.91, 95% CI 1.85-4.58, P<0.001; ARDadj 16.2%, 95% CI 9.8-22.5%, P<0.001), and high ketamine dose (P-for-trend <0.001, ORadj 1.61, 95% CI, 1.43-1.81 for ketamine >0.5 mg kg-1). Concomitant opioid administration mitigated the risk (P-for-interaction <0.001). Ketamine was associated with higher odds of nursing home discharge (ORadj 1.11, 95% CI 1.02-1.21, P=0.012; ARDadj 0.25%, 95% CI 0.05-0.46%, P=0.014). CONCLUSIONS: Ketamine use for procedural sedation was associated with an increased risk of oxygen desaturation and discharge to a nursing home. The effect was dose-dependent and magnified in subgroups of vulnerable patients.
Assuntos
Ketamina , Adulto , Humanos , Ketamina/efeitos adversos , Estudos Retrospectivos , Hospitais , Sistema de Registros , Serviço Hospitalar de Emergência , Oxigênio , Atenção à Saúde , Aceitação pelo Paciente de Cuidados de Saúde , Sedação Consciente/métodos , Hipnóticos e SedativosRESUMO
BACKGROUND & AIMS: Vinyl chloride (VC) monomer is a volatile organic compound commonly used in industry. At high exposure levels, VC causes liver cancer and toxicant-associated steatohepatitis. However, lower exposure levels (i.e., sub-regulatory exposure limits) that do not directly damage the liver, enhance injury caused by Western diet (WD). It is still unknown if the long-term impact of transient low-concentration VC enhances the risk of liver cancer development. This is especially a concern given that fatty liver disease is in and of itself a risk factor for the development of liver cancer. METHODS: C57Bl/6 J mice were fed WD or control diet (CD) for 1 year. During the first 12 weeks of feeding only, mice were also exposed to VC via inhalation at sub-regulatory limit concentrations (<1 ppm) or air for 6 h/day, 5 days/week. RESULTS: Feeding WD for 1 year caused significant hepatic injury, which was exacerbated by VC. Additionally, VC increased the number of tumors which ranged from moderately to poorly differentiated hepatocellular carcinoma (HCC). Transcriptomic analysis demonstrated VC-induced changes in metabolic but also ribosomal processes. Epitranscriptomic analysis showed a VC-induced shift of the modification pattern that has been associated with metabolic disease, mitochondrial dysfunction, and cancer. CONCLUSIONS: These data indicate that VC sensitizes the liver to other stressors (e.g., WD), resulting in enhanced tumorigenesis. These data raise concerns about potential interactions between VC exposure and WD. It also emphasizes that current safety restrictions may be insufficient to account for other factors that can influence hepatotoxicity.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Cloreto de Vinil , Camundongos , Animais , Cloreto de Vinil/toxicidade , Cloreto de Vinil/metabolismo , Transcriptoma , Carcinoma Hepatocelular/patologia , Dieta Ocidental , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Carcinogênese/metabolismo , Transformação Celular Neoplásica/metabolismoRESUMO
BACKGROUND: High-level occupational vinyl chloride (VC) exposures have been associated with hepatic hemangiosarcoma, which typically develops following a long latency period. Although VC is genotoxic, a more comprehensive mode of action has not been determined and diagnostic biomarkers have not been established. The purpose of this study is to address these knowledge gaps through plasma metabolomics. METHODS: Plasma samples from polyvinyl chloride polymerization workers who developed hemangiosarcoma (cases, n = 15) and VC exposure-matched controls (n = 17) underwent metabolomic analysis. Random forest and bioinformatic analyses were performed. RESULTS: Cases and controls had similar demographics and routine liver biochemistries. Mass spectroscopy identified 606 known metabolites. Random forest analysis had an 82% predictive accuracy for group classification. 60 metabolites were significantly increased and 44 were decreased vs. controls. Taurocholate, bradykinin and fibrin degradation product 2 were up-regulated by greater than 80-fold. The naturally occurring anti-angiogenic phenol, 4-hydroxybenzyl alcohol, was down-regulated 5-fold. Top affected ontologies involved: (i) metabolism of bile acids, taurine, cholesterol, fatty acids and amino acids; (ii) inflammation and oxidative stress; and (iii) nicotinic cholinergic signaling. CONCLUSIONS: The plasma metabolome was differentially regulated in polyvinyl chloride workers who developed hepatic hemangiosarcoma. Ontologies potentially involved in hemangiosarcoma pathogenesis and candidate biomarkers were identified.
Assuntos
Biomarcadores/sangue , Hemangiossarcoma/diagnóstico , Neoplasias Hepáticas/diagnóstico , Metaboloma , Doenças Profissionais/diagnóstico , Exposição Ocupacional/efeitos adversos , Cloreto de Polivinila/efeitos adversos , Estudos de Casos e Controles , Hemangiossarcoma/sangue , Hemangiossarcoma/induzido quimicamente , Hemangiossarcoma/epidemiologia , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/epidemiologia , Masculino , Pessoa de Meia-Idade , Doenças Profissionais/sangue , Doenças Profissionais/induzido quimicamente , Doenças Profissionais/epidemiologia , Estados Unidos/epidemiologiaRESUMO
Volatile organic compounds (VOCs), such as vinyl chloride (VC), can be directly toxic at high concentrations. However, we have shown that 'nontoxic' exposures to VC and its metabolite chloroethanol (CE) enhances experimental non-alcoholic fatty liver disease (NAFLD), suggesting an unpredicted interaction. Importantly, VOC exposure has been identified as a potential risk factor for the development of obesity and its sequelae in humans. As there is a known axis between adipose and hepatic tissue in NAFLD, the impact of CE on white adipose tissue (WAT) inflammation and lipolysis was investigated. Mice were administered CE (or vehicle) once, after 10 weeks of being fed high-fat or low-fat diet (LFD). CE significantly enhanced hepatic steatosis and inflammation caused by HFD. HFD significantly increased the size of epididymal fat pads, which was enhanced by CE. The relative size of adipocyte lipid droplets increased by HFD + CE, which was also correlated with increased expression of lipid-associated proteins (e.g., PLINs). CE also enhanced HFD-induced indices of WAT inflammation, and ER stress. Hepatic-derived circulating FGF21, a major modulator of WAT lipolysis, which is hypothesized to thereby regulate hepatic steatosis, was significantly increased by CE in animals fed HFD. Taken together these data support the hypothesis that environmental toxicant exposure can exacerbate the severity of NAFLD/NASH, involving the liver-adipose axis in this process. Specifically, CE enhances local inflammation and alters lipid metabolism and WAT-mediated hepatic steatosis due to changes in WAT lipolysis.
Assuntos
Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cloreto de Vinil/toxicidade , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/induzido quimicamente , Obesidade/metabolismoRESUMO
Vinyl chloride (VC) is a prevalent environmental toxicant that is rapidly metabolized within the liver. Its metabolites have been shown to directly cause hepatic injury at high exposure levels. We have previously reported that VC metabolite, chloroethanol (CE), potentiates liver injury caused by lipopolysaccharide (LPS). Importantly, that study showed that CE alone, while not causing damage per se, was sufficient to alter hepatic metabolism and increase mTOR phosphorylation in mice, suggesting a possible role for the mTOR pathway. Here, we explored the effect of an mTOR inhibitor, rapamycin, in this model. C57BL/6â¯J mice were administered CE, followed by rapamycin 1â¯h and LPS 24â¯h later. As observed previously, the combination of CE and LPS significantly enhanced liver injury, inflammation, oxidative stress, and metabolic dysregulation. Rapamycin attenuated not only inflammation, but also restored the metabolic phenotype and protected against CEâ¯+â¯LPS-induced oxidative stress. Importantly, rapamycin protected against mitochondrial damage and subsequent production of reactive oxygen species (ROS). The protective effect on mitochondrial function by rapamycin was mediated, by restoring the integrity of the electron transport chain at least in part, by blunting the deactivation of mitochondrial c-src, which is involved mitochondrial ROS production by electron transport chain leakage. Taken together, these results further demonstrate a significant role of mTOR-mediated pathways in VC-metabolite induced liver injury and provide further insight into VC-associated hepatic damage. As mTOR mediated pathways are very complex and rapamycin is a more global inhibitor, more specific mTOR (i.e. mTORC1) inhibitors should be considered in future studies.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Cloretos/toxicidade , Etanol/toxicidade , Lipopolissacarídeos/toxicidade , Sirolimo/uso terapêutico , Cloreto de Vinil/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Sirolimo/farmacologia , Cloreto de Vinil/metabolismoRESUMO
Occupational and environmental exposures to industrial chemicals are known to cause hepatotoxicity and liver injury, in humans and in animal models. Historically, research has focused on severe acute liver injury (e.g. fulminant liver failure) or endstage diseases (e.g. cirrhosis and HCC). However, it has become recently recognized that toxicants can cause more subtle changes to the liver. For example, toxicant-associated steatohepatitis, characterized by hepatic steatosis, and inflammation, was recently recognized in an occupational cohort exposed to vinyl chloride. At high occupational levels, toxicants are sufficient to cause liver damage and disease even in healthy subjects with no comorbidities for liver injury. However, it is still largely unknown how exposure to toxicants initiate and possibly more importantly exacerbate liver disease, when combined with other factors, such as underlying non-alcoholic fatty liver disease caused by poor diet and/or obesity. With better understanding of the mechanism(s) and risk factors that mediate the initiation and progression of toxicant-induced liver disease, rational targeted therapy can be developed to better predict risk, as well as to treat or prevent this disease. The purpose of this review is to summarize established and proposed mechanisms of volatile organic compound-induced liver injury and to highlight key signaling events known or hypothesized to mediate these effects.
Assuntos
Hepatopatias/patologia , Fígado/efeitos dos fármacos , Compostos Orgânicos Voláteis/efeitos adversos , Humanos , Fígado/patologiaRESUMO
Obesity, usually caused by high fat diets (HFD), is a major public health issue worldwide, causing obesity associated cardiomyopathy. Moreover, the environmental toxicant vinyl chloride (VC) can exacerbate HFD-induced fatty liver disease. However, whether VC serves to enhance obesity-associated cardiomyopathy remains unclear. This study aims to investigate the interaction of western diet (WD) containing relatively low fat (42%) with VC on cardiac remodeling and its underling mechanisms. Adult male C57BL/6J mice were exposed to WD coinhalation of low-dose VC (<1 ppm/d) for 12 weeks. Results showed that WD feeding for 12 weeks caused slight cardiac systolic dysfunction without significant hypertrophy or fibrosis, even with VC. Nevertheless, WD upregulated NF-κB function and expression of IL-1ß and PAI-1, while VC showed no significant impact on these effects. In contrast, WD together with VC significantly increased the expression of CHOP and TGF-ß1, key markers for endoplasmic reticulum stress and profibrotic cytokine, respectively. In summary, exposure to low-dose of environmental toxicant VC while a WD is consumed for a relatively short time does not have significant impact on cardiac remodeling except for a mild systolic dysfunction of the heart.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Dieta Ocidental/efeitos adversos , Poluentes Ambientais/toxicidade , Coração/efeitos dos fármacos , Miocárdio/metabolismo , Remodelação Ventricular/efeitos dos fármacos , Cloreto de Vinil/efeitos adversos , Fator 4 Ativador da Transcrição/metabolismo , Animais , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Coração/fisiopatologia , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/fisiopatologia , Resistência à Insulina , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Subunidade p50 de NF-kappa B/metabolismo , Obesidade/induzido quimicamente , Obesidade/fisiopatologia , Serpina E2/metabolismo , Fator de Transcrição CHOP/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Alcoholic liver disease (ALD) ranks among major causes of morbidity and mortality. Diet and crosstalk between the gut and liver are important determinants of ALD. We evaluated the effects of different types of dietary fat and ethanol on the gut microbiota composition and metabolic activity and the effect of these changes on liver injury in ALD. Compared with ethanol and a saturated fat diet (medium chain triglycerides enriched), an unsaturated fat diet (corn oil enriched) exacerbated ethanol-induced endotoxemia, liver steatosis, and injury. Major alterations in gut microbiota, including a reduction in Bacteroidetes and an increase in Proteobacteria and Actinobacteria, were seen in animals fed an unsaturated fat diet and ethanol but not a saturated fat diet and ethanol. Compared with a saturated fat diet and ethanol, an unsaturated fat diet and ethanol caused major fecal metabolomic changes. Moreover, a decrease in certain fecal amino acids was noted in both alcohol-fed groups. These data support an important role of dietary lipids in ALD pathogenesis and provide insight into mechanisms of ALD development. A diet enriched in unsaturated fats enhanced alcohol-induced liver injury and caused major fecal metagenomic and metabolomic changes that may play an etiologic role in observed liver injury. Dietary lipids can potentially serve as inexpensive interventions for the prevention and treatment of ALD.
Assuntos
Gorduras Insaturadas na Dieta/metabolismo , Gorduras na Dieta/metabolismo , Etanol/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Hepatopatias Alcoólicas/metabolismo , Animais , Modelos Animais de Doenças , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Triglicerídeos/metabolismoRESUMO
Experimental alcohol-induced liver injury is exacerbated by a high polyunsaturated fat diet rich in linoleic acid. We postulated that bioactive oxidized linoleic acid metabolites (OXLAMs) play a critical role in the development/progression of alcohol-mediated hepatic inflammation and injury. OXLAMs are endogenous ligands for transient receptor potential vanilloid 1 (TRPV1). Herein, we evaluated the role of signaling through TRPV1 in an experimental animal model of alcoholic liver disease (ALD). Chronic binge alcohol administration increased plasma OXLAM levels, specifically 9- and 13-hydroxy-octadecadienoic acids. This effect was associated with up-regulation of hepatic TRPV1. Exposure of hepatocytes to these OXLAMs in vitro resulted in activation of TRPV1 signal transduction with increased intracellular Ca(2+) levels. Genetic depletion of TRPV1 did not blunt hepatic steatosis caused by ethanol, but prevented hepatic injury. TRPV1 deficiency protected from hepatocyte death and prevented the increase in proinflammatory cytokine and chemokine expression, including tumor necrosis factor-α, IL-6, macrophage inflammatory protein-2, and monocyte chemotactic protein 1. TRPV1 depletion markedly blunted ethanol-mediated induction of plasminogen activator inhibitor-1, an important alcohol-induced hepatic inflammation mediator, via fibrin accumulation. This study indicates, for the first time, that TRPV1 receptor pathway may be involved in hepatic inflammatory response in an experimental animal model of ALD. TRPV1-OXLAM interactions appear to play a significant role in hepatic inflammation/injury, further supporting an important role for dietary lipids in ALD.
Assuntos
Hepatopatias Alcoólicas/genética , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/fisiologia , Animais , Consumo Excessivo de Bebidas Alcoólicas/patologia , Caspase 3/metabolismo , Quimiocina CCL2/sangue , Quimiocina CXCL2/sangue , Modelos Animais de Doenças , Etanol/química , Células Hep G2 , Humanos , Inflamação/patologia , Interleucina-6/sangue , Ligantes , Ácido Linoleico/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND: Occupational vinyl chloride (VC) exposures have been associated with toxicant-associated steatohepatitis and liver cancer. Metabolomics has been used to clarify mode of action in drug-induced liver injury but has not been performed following VC exposures. METHODS: Plasma samples from 17 highly exposed VC workers without liver cancer and 27 unexposed healthy volunteers were obtained for metabolite extraction and GC/MS and LC/MS2 analysis. Following ion identification/quantification, Ingenuity pathway analysis was performed. RESULTS: 613 unique named metabolites were identified. Of these, 189 metabolites were increased in the VC exposure group while 94 metabolites were decreased. Random Forest analysis indicated that the metabolite signature could separate the groups with 94% accuracy. VC exposures were associated with increased long chain (including arachidonic acid) and essential (including linoleic acid) fatty acids. Occupational exposure increased lipid peroxidation products including monohydroxy fatty acids (including 13-HODE); fatty acid dicarboxylates; and oxidized arachidonic acid products (including 5,9, and 15-HETE). Carnitine and carnitine esters were decreased, suggesting peroxisomal/mitochondrial dysfunction and alternate modes of lipid oxidation. Differentially regulated metabolites were shown to interact with extracellular-signal-regulated kinase 1/2 (ERK1/2), Akt, AMP-activated protein kinase (AMPK), and the N-Methyl-d-aspartate (NMDA) receptor. The top canonical pathways affected by occupational exposure included tRNA charging, nucleotide degradation, amino acid synthesis/degradation and urea cycle. Methionine and homocysteine was increased with decreased cysteine, suggesting altered 1-carbon metabolism. CONCLUSIONS: Occupational exposure generated a distinct plasma metabolome with markedly altered lipid and amino acid metabolites. ERK1/2, Akt, AMPK, and NMDA were identified as protein targets for vinyl chloride toxicity.
Assuntos
Proteínas Sanguíneas/metabolismo , Metabolômica , Exposição Ocupacional , Cloreto de Polivinila/toxicidade , Adulto , Estudos de Casos e Controles , Humanos , Pessoa de Meia-Idade , Cloreto de Polivinila/síntese químicaRESUMO
BACKGROUND: Vinyl chloride (VC) causes toxicant-associated steatohepatitis at high exposure levels. Recent work by this group suggests that underlying liver disease may predispose the liver to VC hepatotoxicity at lower exposure levels. The most common form of underlying liver disease in the developed world is non-alcoholic fatty liver disease (NAFLD). It is well-known that the type of dietary fat can play an important role in the pathogenesis of NAFLD. However, whether the combination of dietary fat and VC/metabolites promotes liver injury has not been studied. METHODS: Mice were administered chloroethanol (CE - a VC metabolite) or vehicle once, 10weeks after being fed diets rich in saturated fatty acids (HSFA), rich in poly-unsaturated fatty acids (HPUFA), or the respective low-fat control diets (LSFA; LPUFA). RESULTS: In control mice, chloroethanol caused no detectable liver injury, as determined by plasma transaminases and histologic indices of damage. In HSFA-fed mice, chloroethanol increased HSFA-induced liver damage, steatosis, infiltrating inflammatory cells, hepatic expression of proinflammatory cytokines, and markers of endoplasmic reticulum (ER) stress. Moreover, markers of inflammasome activation were increased, while markers of inflammasome inhibition were downregulated. In mice fed HPUFA all of these effects were significantly attenuated. CONCLUSIONS: Chloroethanol promotes inflammatory liver injury caused by dietary fatty acids. This effect is far more exacerbated with saturated fat, versus poly-unsaturated fat; and strongly correlates with a robust activation of the NLRP3 inflammasome in the saturated fed animals only. Taken together these data support the hypothesis that environmental toxicant exposure can exacerbate the severity of NAFLD/NASH.
Assuntos
Gorduras na Dieta/farmacologia , Ácidos Graxos/farmacologia , Fígado/efeitos dos fármacos , Cloreto de Vinil/toxicidade , Animais , Gorduras na Dieta/administração & dosagem , Estresse do Retículo Endoplasmático , Ácidos Graxos/administração & dosagem , Expressão Gênica , Teste de Tolerância a Glucose , Mediadores da Inflamação/metabolismo , Lipídeos/sangue , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
UNLABELLED: Background. The regenerative capacity of the liver is critical for proper responses to injury. Fibrin extracellular matrix (ECM) deposition is a common response to insult and contributes to inflammatory liver injury. However, the role of this matrix in hepatic regeneration has not been determined. OBJECTIVE: The purpose of this study was first to determine the role of fibrin ECM in hepatic regeneration followed by the role of the fibrin-binding αvß3 integrin in mediating this effect. MATERIAL AND METHODS: C57Bl/6J (WT) or PAI-1 knockout (KO) mice underwent 70% partial hepatectomy (PHx); plasma and histologic indices of regeneration were determined, as well as expression of key genes involved in hepatic regeneration. RESULTS: PHx promoted transient fibrin deposition by activating coagulation and concomitantly decreasing fibrinolysis. Inhibiting fibrin deposition, either by blocking thrombin (hirudin) in WT mice or by knocking out PAI-1, was associated with a decrease in hepatocyte proliferation after PHx. This strongly suggested a role for fibrin ECM in liver regeneration. To investigate if αvß3 integrin mediates this action, we tested the effects of the anti-αvß3 cyclic peptide RGDfV in animals after PHx. As was observed with inhibition of fibrin deposition, competitive inhibition of αvß3 integrin delayed regeneration after PHx, while not affecting fibrin deposition. These effects of RGDfV correlated with impaired angiogénesis and STAT3 signaling, as well as transient endothelial dysfunction. In conclusion, these data suggest that αvß3 integrin plays an important role in coordinating hepatocyte division during liver regeneration after PHx via crosstalk with fibrin ECM.
Assuntos
Proliferação de Células , Fibrina/metabolismo , Hepatectomia/métodos , Hepatócitos/metabolismo , Integrina alfaVbeta3/metabolismo , Regeneração Hepática , Fígado/metabolismo , Fígado/cirurgia , Transdução de Sinais , Animais , Coagulação Sanguínea , Proliferação de Células/efeitos dos fármacos , Fibrinólise , Genótipo , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Integrina alfaVbeta3/antagonistas & inibidores , Fígado/efeitos dos fármacos , Fígado/patologia , Regeneração Hepática/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peptídeos Cíclicos/farmacologia , Fenótipo , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de TempoRESUMO
It is known that chronic ethanol significantly impairs liver regeneration. However, the effect of acute ethanol exposure on liver regeneration remains largely unknown. To address this question, C57Bl6/J mice were exposed to acute ethanol (6 g/kg intragastrically) for 3 days, and partial hepatectomy (PHx) was performed 24 h after the last dose. Surprisingly, acute ethanol preexposure promoted liver regeneration. This effect of ethanol did not correlate with changes in expression of cell cycle regulatory genes (e.g., cyclin D1, p21, and p27) but did correlate with protection against the effect of PHx on indices of impaired lipid and carbohydrate metabolism. Ethanol preexposure protected against inhibition of the oxidant-sensitive mitochondrial enzyme, aconitase. The activity of aldehyde dehydrogenase 2 (ALDH2) was significantly increased by ethanol preexposure. The effect of ethanol was blocked by inhibiting (Daidzin) and was mimicked by activating (Alda-1) ALDH2. Lipid peroxides are also substrates for ALDH2; indeed, alcohol preexposure blunted the increase in lipid peroxidation (4OH-nonenal adducts) caused by PHx. Taken together, these data suggest that acute preoperative ethanol exposure "preconditions" the liver to respond more rapidly to regenerate after PHx by activating mitochondrial ALDH2, which prevents oxidative stress in this compartment.
Assuntos
Aldeído Desidrogenase/metabolismo , Etanol/farmacologia , Hepatectomia/métodos , Regeneração Hepática , Aconitato Hidratase/metabolismo , Aldeído-Desidrogenase Mitocondrial , Animais , Citoproteção , Regulação da Expressão Gênica/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Regeneração Hepática/efeitos dos fármacos , Regeneração Hepática/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
Polychlorinated biphenyls (PCBs) are persistent organic pollutants associated with non-alcoholic fatty liver disease (NAFLD) in epidemiologic studies. The purpose of this study was to evaluate the hepatic effects of a PCB mixture, Aroclor 1260, whose composition mimics human bioaccumulation patterns, in a mouse model of diet-induced obesity (DIO). Male C57Bl/6J mice were fed control diet or 42% high fat diet (HFD) and exposed to Aroclor 1260 (20mg/kg or 200mg/kg in corn oil) for 12weeks. A glucose tolerance test was performed; plasma/tissues were obtained at necropsy for measurements of adipocytokine levels, histology, and gene expression. Aroclor 1260 exposure was associated with decreased body fat in HFD-fed mice but had no effect on blood glucose/lipid levels. Paradoxically, Aroclor 1260+HFD co-exposed mice demonstrated increased hepatic inflammatory foci at both doses while the degree of steatosis did not change. Serum cytokines, ALT levels and hepatic expression of IL-6 and TNFα were increased only at 20mg/kg, suggesting an inhibition of pro-inflammatory cytokine production at the 200mg/kg exposure. Aroclor 1260 induced hepatic expression of cytochrome P450s including Cyp3a11 (Pregnane-Xenobiotic Receptor target) and Cyp2b10 (constitutive androstane receptor target) but Cyp2b10 inducibility was diminished with HFD-feeding. Cyp1a2 (aryl hydrocarbon Receptor target) was induced only at 200mg/kg. In summary, Aroclor 1260 worsened hepatic and systemic inflammation in DIO. The results indicated a bimodal response of PCB-diet interactions in the context of inflammation which could potentially be explained by xenobiotic receptor activation. Thus, PCB exposure may be a relevant "second hit" in the transformation of steatosis to steatohepatitis.
Assuntos
Arocloros/toxicidade , Poluentes Ambientais/toxicidade , Fígado Gorduroso/induzido quimicamente , Obesidade/induzido quimicamente , Adipocinas/metabolismo , Tecido Adiposo/patologia , Animais , Hidrocarboneto de Aril Hidroxilases/biossíntese , Hidrocarboneto de Aril Hidroxilases/genética , Glicemia/metabolismo , Colesterol/metabolismo , Citocromo P-450 CYP3A/biossíntese , Citocromo P-450 CYP3A/genética , Família 2 do Citocromo P450 , Dieta , Fígado Gorduroso/patologia , Expressão Gênica/efeitos dos fármacos , Teste de Tolerância a Glucose , Inflamação/induzido quimicamente , Inflamação/patologia , Fígado/patologia , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica , Obesidade/patologia , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Hidrocarboneto Arílico/biossíntese , Receptores de Hidrocarboneto Arílico/genética , Esteroide Hidroxilases/biossíntese , Esteroide Hidroxilases/genética , Receptor 4 Toll-Like/biossíntese , Receptor 4 Toll-Like/genética , Triglicerídeos/metabolismoRESUMO
BACKGROUND: Protein kinase C epsilon (PKCε) has been shown to play a role in experimental steatosis by acute alcohol. The "two-hit" hypothesis implies that preventing steatosis should blunt more advanced liver damage (e.g., inflammation and necrosis). However, the role of PKCε in these pathologies is not yet known. The goal of this current work was to address this question in a model of chronic alcohol exposure using antisense oligonucleotides (ASO) against PKCε. METHODS: Accordingly, PKCε ASO- and saline-treated mice were fed high-fat control or ethanol (EtOH)-containing enteral diets for 4 weeks. RESULTS: Chronic EtOH exposure significantly elevated hepatic lipid pools as well as activated PKCε. The PKCε ASO partially blunted the increases in hepatic lipids caused by EtOH. Administration of PKCε ASO also completely prevented the increase in the expression of fatty acid synthase, and tumor necrosis factor α caused by EtOH. Despite these protective effects, the PKCε ASO was unable to prevent the increases in inflammation and necrosis caused by chronic EtOH. These latter results correlated with an inability of the PKCε ASO to blunt the up-regulation of plasminogen activator inhibitor-1 (PAI-1) and the accumulation of fibrin. Importantly, PAI-1 has been previously shown to more robustly mediate inflammation and necrosis (vs. steatosis) after chronic EtOH exposure. CONCLUSIONS: This study identifies a novel potential mechanism where EtOH, independent of steatosis, can contribute to liver damage. These results also suggest that PAI-1 and fibrin accumulation may be at the center of this PKCε-independent pathway.
Assuntos
Depressores do Sistema Nervoso Central/efeitos adversos , Etanol/efeitos adversos , Fígado Gorduroso Alcoólico/etiologia , Fígado/patologia , Proteína Quinase C-épsilon/metabolismo , Animais , Biomarcadores/sangue , Peso Corporal/efeitos dos fármacos , Depressores do Sistema Nervoso Central/urina , Diglicerídeos/metabolismo , Ativação Enzimática/efeitos dos fármacos , Etanol/urina , Fígado Gorduroso Alcoólico/enzimologia , Fibrina/metabolismo , Expressão Gênica/efeitos dos fármacos , Hepatite Alcoólica/etiologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NecroseRESUMO
BACKGROUND: Alcohol-associated hepatitis (AH) is plagued with high mortality and difficulty in identifying at-risk patients. The extracellular matrix undergoes significant remodeling during inflammatory liver injury and could potentially be used for mortality prediction. METHODS: EDTA plasma samples were collected from patients with AH (n = 62); Model for End-Stage Liver Disease score defined AH severity as moderate (12-20; n = 28) and severe (>20; n = 34). The peptidome data were collected by high resolution, high mass accuracy UPLC-MS. Univariate and multivariate analyses identified differentially abundant peptides, which were used for Gene Ontology, parent protein matrisomal composition, and protease involvement. Machine-learning methods were used to develop mortality predictors. RESULTS: Analysis of plasma peptides from patients with AH and healthy controls identified over 1600 significant peptide features corresponding to 130 proteins. These were enriched for extracellular matrix fragments in AH samples, likely related to the turnover of hepatic-derived proteins. Analysis of moderate versus severe AH peptidomes was dominated by changes in peptides from collagen 1A1 and fibrinogen A proteins. The dominant proteases for the AH peptidome spectrum appear to be CAPN1 and MMP12. Causal graphical modeling identified 3 peptides directly linked to 90-day mortality in >90% of the learned graphs. These peptides improved the accuracy of mortality prediction over the Model for End-Stage Liver Disease score and were used to create a clinically applicable mortality prediction assay. CONCLUSIONS: A signature based on plasma peptidome is a novel, noninvasive method for prognosis stratification in patients with AH. Our results could also lead to new mechanistic and/or surrogate biomarkers to identify new AH mechanisms.
Assuntos
Matriz Extracelular , Hepatite Alcoólica , Humanos , Masculino , Prognóstico , Feminino , Hepatite Alcoólica/sangue , Hepatite Alcoólica/mortalidade , Matriz Extracelular/metabolismo , Pessoa de Meia-Idade , Adulto , Peptídeos/sangue , Biomarcadores/sangue , Índice de Gravidade de Doença , Aprendizado de Máquina , Estudos de Casos e Controles , ProteômicaRESUMO
Olanzapine (OLZ), an effective treatment of schizophrenia and other disorders, causes weight gain and metabolic syndrome. Most studies to date have focused on the potential effects of OLZ on the central nervous system's mediation of weight; however, peripheral changes in liver or other key metabolic organs may also play a role in the systemic effects of OLZ. Thus, the purpose of this study was to investigate the effects of OLZ on hepatic metabolism in a mouse model of OLZ exposure. Female C57Bl/6J mice were administered OLZ (8 mg/kg per day) or vehicle subcutaneously by osmotic minipumps for 28 days. Liver and plasma were taken at sacrifice for biochemical analyses and for comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry metabolomics analysis. OLZ increased body weight, fat pad mass, and liver-to-body weight ratio without commensurate increase in food consumption, indicating that OLZ altered energy expenditure. Expression and biochemical analyses indicated that OLZ induced anaerobic glycolysis and caused a pseudo-fasted state, which depleted hepatic glycogen reserves. OLZ caused similar effects in cultured HepG2 cells, as determined by Seahorse analysis. Metabolomic analysis indicated that OLZ increased hepatic concentrations of amino acids that can alter metabolism via the mTOR pathway; indeed, hepatic mTOR signaling was robustly increased by OLZ. Interestingly, OLZ concomitantly activated AMP-activated protein kinase (AMPK) signaling. Taken together, these data suggest that disturbances in glucose and lipid metabolism caused by OLZ in liver may be mediated, at least in part, via simultaneous activation of both catabolic (AMPK) and anabolic (mammalian target of rapamycin) pathways, which yields new insight into the metabolic side effects of this drug.
Assuntos
Antipsicóticos/metabolismo , Benzodiazepinas/metabolismo , Glicemia/metabolismo , Metabolismo dos Lipídeos/fisiologia , Fígado/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Antipsicóticos/administração & dosagem , Benzodiazepinas/administração & dosagem , Glicemia/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Feminino , Bombas de Infusão Implantáveis , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Olanzapina , Pressão Osmótica , Aumento de Peso/efeitos dos fármacos , Aumento de Peso/fisiologiaRESUMO
Hepatotoxicity is the most common organ injury due to occupational and environmental exposures to industrial chemicals. A wide range of liver pathologies ranging from necrosis to cancer have been observed following chemical exposures both in humans and in animal models. Toxicant-associated fatty liver disease (TAFLD) is a recently named form of liver injury pathologically similar to alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). Toxicant-associated steatohepatitis (TASH) is a more severe form of TAFLD characterized by hepatic steatosis, inflammatory infiltrate, and in some cases, fibrosis. While subjects with TASH have exposures to industrial chemicals, such as vinyl chloride, they do not have traditional risk factors for fatty liver such as significant alcohol consumption or obesity. Conventional biomarkers of hepatotoxicity including serum alanine aminotransferase activity may be normal in TASH, making screening problematic. This article examines selected chemical exposures associated with TAFLD in human subjects or animal models and concisely reviews the closely related NAFLD and ALD.
Assuntos
Fígado Gorduroso/induzido quimicamente , Doenças Profissionais/induzido quimicamente , Animais , Biomarcadores , Histocitoquímica , Humanos , Exposição Ocupacional/efeitos adversos , Fatores de Risco , Cloreto de Vinil/intoxicação , Cloreto de Vinil/toxicidadeRESUMO
Alterations in physiological processes in pancreas have been associated with various metabolic dysfunctions and can result from environmental exposures, such as chemicals and diet. It was reported that environmental vinyl chloride (VC) exposure, a common industrial organochlorine and environmental pollutant, significantly exacerbated metabolic-related phenotypes in mice fed concurrently with high-fat diet (HFD) but not low-fat diet (LFD). However, little is known about the role of the pancreas in this interplay, especially at a proteomic level. The present study was undertaken to examine the protein responses to VC exposure in pancreas tissues of C57BL/6J mice fed LFD or HFD, with focus on the investigation of protein expression and/or phosphorylation levels of key protein biomarkers of carbohydrate, lipid, and energy metabolism, oxidative stress and detoxification, insulin secretion and regulation, cell growth, development, and communication, immunological responses and inflammation, and biomarkers of pancreatic diseases and cancers. We found that the protein alterations may indicate diet-mediated susceptibility in mouse pancreas induced by HFD to concurrent exposure of low levels of inhaled VC. These proteome biomarkers may lead to a better understanding of pancreas-mediated adaptive or adverse response and susceptibility to metabolic disease.