RESUMO
BACKGROUND AND AIMS: Alcohol-associated liver disease (ALD) pathologies include steatosis, inflammation, and injury, which may progress to fibrosis, cirrhosis, and cancer. The liver receives ~60% of fatty acids from adipose tissue triglyceride hydrolysis, but the role of this lipolytic pathway in ALD development has not been directly examined in any genetic animal models with selective inactivation of adipose lipolysis. APPROACH AND RESULTS: Using adipose-specific comparative gene identification-58 (CGI-58) knockout (FAT-KO) mice, a model of impaired adipose lipolysis, we show that mice deficient in adipose lipolysis are almost completely protected against ethanol-induced hepatic steatosis and lipid peroxidation when subjected to the National Institute on Alcohol Abuse and Alcoholism chronic and binge ethanol feeding model. This is unlikely due to reduced lipid synthesis because this regimen of ethanol feeding down-regulated hepatic expression of lipogenic genes similarly in both genotypes. In the pair-fed group, FAT-KO relative to control mice displayed increased hepatocyte injury, neutrophil infiltration, and activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) in the liver; and none of these were exacerbated by ethanol feeding. Activation of STAT3 is associated with a marked increase in hepatic leptin receptor mRNA expression and adipose inflammatory cell infiltration. CONCLUSIONS: Our findings establish a critical role of adipose lipolysis in driving hepatic steatosis and oxidative stress during ALD development.
Assuntos
Fígado Gorduroso , Hepatopatias Alcoólicas , Estados Unidos , Camundongos , Animais , Etanol/farmacologia , Lipólise , Modelos Animais de Doenças , National Institute on Alcohol Abuse and Alcoholism (U.S.) , Fígado Gorduroso/metabolismo , Fígado/patologia , Hepatopatias Alcoólicas/metabolismo , Camundongos Endogâmicos C57BLRESUMO
The epidemic of overweight and obesity underlies many common metabolic diseases. Approaches aimed to reduce energy intake and/or stimulate energy expenditure represent potential strategies to control weight gain. Adipose tissue is a major energy balancing organ. It can be classified as white adipose tissue (WAT) and brown adipose tissue (BAT). While WAT stores excess metabolic energy, BAT dissipates it as heat via adaptive thermogenesis. WAT also participates in thermogenesis by providing thermogenic fuels and by directly generating heat after browning. Browned WAT resembles BAT morphologically and metabolically and is classified as beige fat. Like BAT, beige fat can produce heat. Human adults have BAT-like or beige fat. Recruitment and activation of this fat type have the potential to increase energy expenditure, thereby countering against obesity and its metabolic complications. Given this, agents capable of inducing WAT browning have recently attracted broad attention from biomedical, nutritional and pharmaceutical societies. In this review, we summarize natural bioactive compounds that have been shown to promote beige adipocyte recruitment and activation in animals and cultured cells. We also discuss potential molecular mechanisms for each compound to induce adipose browning and metabolic benefits.
Assuntos
Tecido Adiposo Branco/efeitos dos fármacos , Obesidade/tratamento farmacológico , Compostos Fitoquímicos/farmacologia , Termogênese/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Humanos , Obesidade/metabolismo , Compostos Fitoquímicos/uso terapêuticoRESUMO
The heart primarily uses fatty acids as energy substrates. Adipose lipolysis is a major source of fatty acids, particularly under stress conditions. In this study, we showed that mice with selective inactivation of the lipolytic coactivator comparative gene identification-58 (CGI-58) in adipose tissue (FAT-KO mice), relative to their littermate controls, had lower circulating FA levels in the fed and fasted states due to impaired adipose lipolysis. They preferentially utilized carbohydrates as energy fuels and were more insulin sensitive and glucose tolerant. Under cold stress, FAT-KO versus control mice had >10-fold increases in glucose uptake in the hearts but no increases in other tissues examined. Plasma concentrations of atrial natriuretic peptide and cardiac mRNAs for atrial and brain-type natriuretic peptides, two sensitive markers of cardiac remodeling, were also elevated. After one week of cold exposure, FAT-KO mice showed reduced cardiac expression of several mitochondrial oxidative phosphorylation proteins. After one month of cold exposure, hearts of these animals showed depressed functions, reduced SERCA2 protein, and increased proteins for MHC-ß, collagen I proteins, Glut1, Glut4 and phospho-AMPK. Thus, CGI-58-dependent adipose lipolysis critically regulates cardiac metabolism and function, especially during cold adaptation. The adipose-heart axis may be targeted for the management of cardiac dysfunction.
Assuntos
Aclimatação , Resposta ao Choque Frio , Glucose/metabolismo , Lipólise , Mitocôndrias Cardíacas/metabolismo , Miocárdio/metabolismo , Animais , Caderinas/deficiência , Caderinas/metabolismo , Glucose/genética , Camundongos , Camundongos Knockout , Mitocôndrias Cardíacas/genéticaRESUMO
OBJECTIVE: We investigated the effects of chronic waterpipe (WP) smoke on pulmonary function and immune response in a murine model using a research-grade WP and the effects of acute exposure on the regulation of immediate-early genes (IEGs). METHODS: WP smoke was generated using three WP smoke puffing regimens based on the Beirut regimen. WP smoke samples generated under these puffing regimens were quantified for nicotine concentration. Mice were chronically exposed for 6 months followed by assessment of pulmonary function and airway inflammation. Transcriptomic analysis using RNAseq was conducted after acute exposure to characterise the IEG response. These biomarkers were then compared with those generated after exposure to dry smoke (without water added to the WP bowl). RESULTS: We determined that nicotine composition in WP smoke ranged from 0.4 to 2.5 mg per puffing session. The lung immune response was sensitive to the incremental severity of chronic exposure, with modest decreases in airway inflammatory cells and chemokine levels compared with air-exposed controls. Pulmonary function was unmodified by chronic WP exposure. Acute WP exposure was found to activate the immune response and identified known and novel IEG as potential biomarkers of WP exposure. CONCLUSION: Chronic exposure to WP smoke leads to immune suppression without significant changes to pulmonary function. Transcriptomic analysis of the lung after acute exposure to WP smoke showed activation of the immune response and revealed IEGs that are common to WP and dry smoke, as well as pools of IEGs unique to each exposure, identifying potential biomarkers specific to WP exposure.
Assuntos
Genes Precoces , Pulmão/imunologia , Nicotina/análise , Fumar Cachimbo de Água/imunologia , Animais , Biomarcadores/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Cachimbos de ÁguaRESUMO
BACKGROUND AND AIMS: Alcohol-associated liver disease (ALD) and NAFLD often coexist in Western societies that consume energy-rich and cholesterol-containing Western diets. Increased rates of ALD mortality in young people in these societies are likely attributable to binge drinking. It is largely unknown how alcohol binge causes liver damage in the setting of Western diets. APPROACH AND RESULTS: In this study, we showed that a single ethanol binge (5 g/kg body weight) induced severe liver injury as shown by marked increases in serum activities of the 2 aminotransferases AST and ALT in C57BL/6J mice that have been fed a Western diet for 3 weeks. The Western diet plus binge ethanol-fed mice also displayed severe lipid droplet deposition and high contents of triglycerides and cholesterol in the liver, which were associated with increased lipogenic and reduced fatty acid oxidative gene expression. These animals had the highest Cxcl1 mRNA expression and myeloperoxidase (MPO)-positive neutrophils in the liver. Their hepatic ROS and lipid peroxidation were the highest, but their hepatic levels of mitochondrial oxidative phosphorylation proteins remained largely unaltered. Hepatic levels of several ER stress markers, including mRNAs for CHOP, ERO1A, ERO1B, BIM, and BIP, as well as Xbp1 splicing and proteins for BIP/GRP78 and IRE-α were also the highest in these animals. Interestingly, Western diet feeding for 3 weeks or ethanol binge dramatically increased hepatic caspase 3 cleavage, and the combination of the 2 did not further increase it. Thus, we successfully established a murine model of acute liver injury by mimicking human diets and binge drinking. CONCLUSIONS: This simple Western diet plus single ethanol binge model recapitulates major hepatic phenotypes of ALD, including steatosis and steatohepatitis characterized by neutrophil infiltration, oxidative stress, and ER stress.
Assuntos
Consumo Excessivo de Bebidas Alcoólicas , Hepatopatias Alcoólicas , Hepatopatia Gordurosa não Alcoólica , Humanos , Animais , Camundongos , Adolescente , Camundongos Endogâmicos C57BL , Etanol/toxicidade , Dieta Ocidental/efeitos adversos , Consumo Excessivo de Bebidas Alcoólicas/complicações , Hepatopatia Gordurosa não Alcoólica/etiologiaRESUMO
This study evaluated the antilipogenic and anti-inflammatory effects of Codonopsis lanceolata (C. lanceolata) root extract in mice with alcohol-induced fatty liver and elucidated its underlying molecular mechanisms. Ethanol was introduced into the liquid diet by mixing it with distilled water at 5% (wt/v), providing 36% of the energy, for nine weeks. Among the three different fractions prepared from the C. lanceolata root, the C. lanceolata methanol extract (CME) exhibited the most remarkable attenuation of alcohol-induced fatty liver with respect to various parameters such as hepatic free fatty acid concentration, body weight loss, and hepatic accumulations of triglyceride and cholesterol. The hepatic gene and protein expression levels were analysed via RT-PCR and Western blotting, respectively. CME feeding significantly restored the ethanol-induced downregulation of the adiponectin receptor (adipoR) 1 and of adipoR2, along with their downstream molecules. Furthermore, the study data showed that CME feeding dramatically reversed ethanol-induced hepatic upregulation of toll-like receptor- (TLR-) mediated signaling cascade molecules. These results indicate that the beneficial effects of CME against alcoholic fatty livers of mice appear to be with adenosine- and adiponectin-mediated regulation of hepatic steatosis and TLR-mediated modulation of hepatic proinflammatory responses.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Codonopsis/química , Fígado Gorduroso Alcoólico/prevenção & controle , Reguladores do Metabolismo de Lipídeos/administração & dosagem , Extratos Vegetais/administração & dosagem , Adenosina/genética , Adenosina/metabolismo , Animais , Colesterol/metabolismo , Modelos Animais de Doenças , Etanol/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Triglicerídeos/metabolismoRESUMO
BACKGROUND & AIMS: Oleuropein, a secoiridoid derived from olives and olive oil, has been known to possess antimicrobial, antioxidative, and anticancer activities. The purpose of the present study was to determine whether oleuropein has a protective effect against hepatic steatosis induced by a high fat diet (HFD) and to elucidate its underlying molecular mechanisms in mice. METHODS: Male C57BL/6N mice were fed a normal diet (ND), HFD, or an oleuropein-supplemented diet (OSD) for 10 weeks. The plasma and hepatic lipid levels were determined, and the hepatic gene and protein expression levels were analysed via RT-PCR and Western blotting, respectively. RESULTS: The supplementation of HFD with oleuropein reversed the HFD-induced increases in liver weight along with plasma and hepatic lipid levels in mice. The expression of Wnt10b inhibitor genes, such as secreted firizzed-related sequence protein 5 and dickkopf homolog 2, was downregulated, whereas the ß-catenin protein expression was upregulated in the liver of OSD-fed mice compared to HFD-fed mice. Fibroblast growth factor receptor 1 (FGFR1), phosphoextracellular-signal-regulated kinase 1/2, cyclin D, and E2F transcription factor 1, along with several key transcription factors and their target genes involved in adipogenesis, were downregulated by oleuropein. OSD-fed mice exhibited decreased expression of the toll-like-receptor-(TLR)-mediated signaling molecules (TLR2, TLR4, and myeloid differentiation primary-response gene 88) and proinflammatory cytokines, in their livers, as compared to HFD mice. CONCLUSIONS: These results suggest that the protective effects of oleuropein against HFD-induced hepatic steatosis in mice appear to be associated with the Wnt10b- and FGFR1-mediated signaling cascades involved in hepatic lipogenesis, along with the TLR2- and TLR4-mediated signaling implicated in hepatic steatosis.
Assuntos
Antioxidantes/farmacologia , Gorduras na Dieta/farmacologia , Fígado/efeitos dos fármacos , Piranos/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Gorduras na Dieta/sangue , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/patologia , Fígado Gorduroso/fisiopatologia , Expressão Gênica/fisiologia , Glucosídeos Iridoides , Iridoides , Lipogênese/genética , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Cirrose Hepática/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica , Tamanho do Órgão/efeitos dos fármacos , Transdução de Sinais/fisiologia , Receptores Toll-Like/metabolismo , beta Catenina/metabolismoRESUMO
Air pollution involving particulate matter smaller than 2.5 µm in size (PM2.5) is the world's leading environmental risk factor contributing to mortality through cardiometabolic pathways. In this study, we modeled early life exposure using chow-fed C57BL/6J male mice that were exposed to real-world inhaled, concentrated PM2.5 (~10 times ambient levels/~60-120 µg/m3) or filtered air over a 14-week period. We investigated the effects of PM2.5 on phenotype, the transcriptome, and chromatin accessibility and compared these with the effects of a prototypical high-fat diet (HFD) as well as cessation of exposure on phenotype reversibility. Exposure to PM2.5 impaired glucose and insulin tolerance and reduced energy expenditure and 18FDG-PET uptake in brown adipose tissue. Multiple differentially expressed gene clusters in pathways involving metabolism and circadian rhythm were noted in insulin-responsive tissues. Although the magnitude of transcriptional change detected with PM2.5 exposure was lower than that observed with a HFD, the degree of alteration in chromatin accessibility after PM2.5 exposure was significant. The novel chromatin remodeler SMARCA5 (SWI/SNF complex) was regulated in response to PM2.5 exposure, the cessation of which was associated with a reversal of insulin resistance and restoration of chromatin accessibility and nucleosome positioning near transcription start sites, as well as a reversal of exposure-induced changes in the transcriptome, including SMARCA5. These changes indicate pliable epigenetic control mechanisms following cessation of exposure.
Assuntos
Tecido Adiposo Marrom , Poluentes Atmosféricos/toxicidade , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/efeitos dos fármacos , Exposição Ambiental/efeitos adversos , Resistência à Insulina , Adenosina Trifosfatases/metabolismo , Tecido Adiposo Marrom/diagnóstico por imagem , Tecido Adiposo Marrom/metabolismo , Animais , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Proteínas Cromossômicas não Histona/metabolismo , Fluordesoxiglucose F18/farmacologia , Camundongos , Tomografia por Emissão de Pósitrons , Transcriptoma/efeitos dos fármacosRESUMO
Chronic nutrient excess leads to metabolic disorders and insulin resistance. Activation of stress-responsive pathways via Nrf2 activation contributes to energy metabolism regulation. Here, inducible activation of Nrf2 in mice and transgenesis of the Nrf2 target, NQO1, conferred protection from diet-induced metabolic defects through preservation of glucose homeostasis, insulin sensitivity, and lipid handling with improved physiological outcomes. NQO1-RNA interaction mediated the association with and inhibition of the translational machinery in skeletal muscle of NQO1 transgenic mice. NQO1-Tg mice on high-fat diet had lower adipose tissue macrophages and enhanced expression of lipogenic enzymes coincident with reduction in circulating and hepatic lipids. Metabolomics data revealed a systemic metabolic signature of improved glucose handling, cellular redox, and NAD+ metabolism while label-free quantitative mass spectrometry in skeletal muscle uncovered a distinct diet- and genotype-dependent acetylation pattern of SIRT3 targets across the core of intermediary metabolism. Thus, under nutritional excess, NQO1 transgenesis preserves healthful benefits.
RESUMO
The aim of present study was to investigate the anti-obesity effect of Ilex paraguariensis extract and its molecular mechanism in rats rendered obese by a high-fat diet (HFD). I. paraguariensis extract supplementation significantly lowered body weight, visceral fat-pad weights, blood and hepatic lipid, glucose, insulin, and leptin levels of rats administered HFD. Feeding I. paraguariensis extract reversed the HFD-induced downregulation of the epididymal adipose tissue genes implicated in adipogenesis or thermogenesis, such as peroxisome proliferators' activated receptor gamma2, adipocyte fatty acid binding protein, sterol-regulatory-element-binding protein-1c, fatty acid synthase, HMG-CoA reductase, uncoupling protein 2, and uncoupling protein 3. Dietary supplementation with I. paraguariensis extract protected rats from the HFD-induced decreases in the phospho-AMP-activated protein kinase (AMPK)/AMPK and phospho-acetyl-CoA carboxylase (ACC)/ACC protein ratio related to fatty acid oxidation in the edipidymal adipose tissue. The present study reports that the I. paraguariensis extract can have a protective effect against a HFD-induced obesity in rats through an enhanced expression of uncoupling proteins and elevated AMPK phosphorylation in the visceral adipose tissue.
Assuntos
Adenilato Quinase/metabolismo , Gorduras na Dieta/administração & dosagem , Ilex paraguariensis , Gordura Intra-Abdominal/efeitos dos fármacos , Obesidade/tratamento farmacológico , Extratos Vegetais/farmacologia , Animais , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Indole-3-carbinol (I3C), found in Brassica family vegetables, exhibits antioxidant, anti-inflammatory, and anti-cancerous properties. Here, we aimed to evaluate the preventive effects of I3C against ethanol (EtOH)-induced liver injury and study the protective mechanism(s) by using the well-established chronic-plus-binge alcohol exposure model. The preventive effects of I3C were evaluated by conducting various histological, biochemical, and real-time PCR analyses in mouse liver, adipose tissue, and colon, since functional alterations of adipose tissue and intestine can also participate in promoting EtOH-induced liver damage. Daily treatment with I3C alleviated EtOH-induced liver injury and hepatocyte apoptosis, but not steatosis, by attenuating elevated oxidative stress, as evidenced by the decreased levels of hepatic lipid peroxidation, hydrogen peroxide, CYP2E1, NADPH-oxidase, and protein acetylation with maintenance of mitochondrial complex I, II, and III protein levels and activities. I3C also restored the hepatic antioxidant capacity by preventing EtOH-induced suppression of glutathione contents and mitochondrial aldehyde dehydrogenase-2 activity. I3C preventive effects were also achieved by attenuating the increased levels of hepatic proinflammatory cytokines, including IL1ß, and neutrophil infiltration. I3C also attenuated EtOH-induced gut leakiness with decreased serum endotoxin levels through preventing EtOH-induced oxidative stress, apoptosis of enterocytes, and alteration of tight junction protein claudin-1. Furthermore, I3C alleviated adipose tissue inflammation and decreased free fatty acid release. Collectively, I3C prevented EtOH-induced liver injury via attenuating the damaging effect of ethanol on the gut-liver-adipose tissue axis. Therefore, I3C may also have a high potential for translational research in treating or preventing other types of hepatic injury associated with oxidative stress and inflammation.
Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas/patologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/prevenção & controle , Etanol/efeitos adversos , Indóis/farmacologia , Alcoolismo/patologia , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Colo/efeitos dos fármacos , Modelos Animais de Doenças , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Masculino , Camundongos Endogâmicos C57BL , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Estresse Oxidativo/efeitos dos fármacos , Paniculite/patologia , Paniculite/prevenção & controleRESUMO
The effects of high (H)-fructose (FR) diet (D) (HFRD) on hepatic lipid homeostasis, oxidative stress, inflammation and hepatocyte apoptosis were investigated in 6-week old female C57BL/6J mice fed a regular chow (ContD) or HFRD (35% fructose-derived calories) for 3 weeks. HFRD-fed mice exhibited increased levels of hepatic steatosis with a significant elevation of serum levels of triglyceride, cholesterol and TNFα compared to ContD-fed mice (P<0.05). HFRD-fed mice exhibited â¼2.7- fold higher levels FAS along with significantly decreased protein levels of adiponection-R2 (â¼30%), P-AMPK (â¼60%), P-ACC (â¼70%) and RXR-α (â¼55%), suggesting decreased hepatic fat oxidation compared to controls. Interestingly, hepatic fatty acid uptake into hepatocytes and lipolysis were significantly increased in HFRD-fed mice, as shown by decreased CD36 and fatty acid transporter protein-2, and increased adipose triglyceride lipase, respectively (P<0.05). Increased hepatic levels of iNOS and GSSG/GSH suggest elevated oxidative stress with a higher number of macrophages in the adipose tissue in HFRD-fed mice (P<0.05). Significantly elevated rates of hepatocyte apoptosis (â¼2.4-fold), as determined by TUNEL analysis with increased Bax/Bcl2 ratio and PARP-1 levels (â¼2- and 1.5-fold, respectively), were observed in HFRD-fed mice. Thus, HFRD exposure increased hepatic steatosis accompanied by oxidative stress and inflammation, leading to hepatocyte apoptosis.
Assuntos
Frutose/efeitos adversos , Hepatócitos/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Estresse Oxidativo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Feminino , Glutationa/metabolismo , Hepatócitos/metabolismo , Hepatócitos/patologia , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Paniculite/induzido quimicamente , Paniculite/metabolismo , Estearoil-CoA Dessaturase/metabolismo , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Receptor fas/metabolismoRESUMO
The aim of this study was to investigate the role of cytochrome P450-2E1 (CYP2E1) in aging-dependent kidney damage since it is poorly understood. Young (7 weeks) and aged female (16-17 months old) wild-type (WT) and Cyp2e1-null mice were used. Kidney histology showed that aged WT mice exhibited typical signs of kidney aging such as cell vacuolation, inflammatory cell infiltration, cellular apoptosis, glomerulonephropathy, and fibrosis, along with significantly elevated levels of renal TNF-α and serum creatinine than all other groups. Furthermore, the highest levels of renal hydrogen peroxide, protein carbonylation and nitration were observed in aged WT mice. These increases in the aged WT mice were accompanied by increased levels of iNOS and mitochondrial nitroxidative stress through altered amounts and activities of the mitochondrial complex proteins and significantly reduced levels of the antioxidant glutathione (GSH). In contrast, the aged Cyp2e1-null mice exhibited significantly higher antioxidant capacity with elevated heme oxygenase-1 and catalase activities compared to all other groups, while maintaining normal GSH levels with significantly less mitochondrial nitroxidative stress compared to the aged WT mice. Thus, CYP2E1 is important in causing aging-related kidney damage most likely through increasing nitroxidative stress and that CYP2E1 could be a potential target in preventing aging-related kidney diseases.
Assuntos
Citocromo P-450 CYP2E1/metabolismo , Nefropatias/enzimologia , Estresse Oxidativo , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Antioxidantes/metabolismo , Apoptose , Citocromo P-450 CYP2E1/genética , Feminino , Glutationa/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Nefropatias/genética , Nefropatias/metabolismo , Nefropatias/fisiopatologia , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Carbonilação Proteica , Fator de Necrose Tumoral alfaRESUMO
Alcoholic fatty liver disease (AFLD) and non-alcoholic fatty liver disease (NAFLD) are two pathological conditions that are spreading worldwide. Both conditions are remarkably similar with regard to the pathophysiological mechanism and progression despite different causes. Oxidative stressinduced mitochondrial dysfunction through post-translational protein modifications and/or mitochondrial DNA damage has been a major risk factor in both AFLD and NAFLD development and progression. Cytochrome P450-2E1 (CYP2E1), a known important inducer of oxidative radicals in the cells, has been reported to remarkably increase in both AFLD and NAFLD. Interestingly, CYP2E1 isoforms expressed in both endoplasmic reticulum (ER) and mitochondria, likely lead to the deleterious consequences in response to alcohol or in conditions of NAFLD after exposure to high fat diet (HFD) and in obesity and diabetes. Whether CYP2E1 in both ER and mitochondria work simultaneously or sequentially in various conditions and whether mitochondrial CYP2E1 may exert more pronounced effects on mitochondrial dysfunction in AFLD and NAFLD are unclear. The aims of this review are to briefly describe the role of CYP2E1 and resultant oxidative stress in promoting mitochondrial dysfunction and the development or progression of AFLD and NAFLD, to shed a light on the function of the mitochondrial CYP2E1 as compared with the ER-associated CYP2E1. We finally discuss translational research opportunities related to this field.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Citocromo P-450 CYP2E1/metabolismo , Mitocôndrias/metabolismo , Animais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Humanos , Peroxidação de Lipídeos , Fígado/metabolismo , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo , Processamento de Proteína Pós-Traducional , Transdução de SinaisRESUMO
Cytochrome P450-2E1 (CYP2E1) increases oxidative stress. High hepatic cholesterol causes non-alcoholic steatohepatitis (NASH) and fibrosis. Thus, we aimed to study the role of CYP2E1 in promoting liver fibrosis by high cholesterol-containing fast-food (FF). Male wild-type (WT) and Cyp2e1-null mice were fed standard chow or FF for 2, 12, and 24 weeks. Various parameters of liver fibrosis and potential mechanisms such as oxidative and endoplasmic reticulum (ER) stress, inflammation, and insulin resistance (IR) were studied. Indirect calorimetry was also used to determine metabolic parameters. Liver histology showed that only WT fed FF (WT-FF) developed NASH and fibrosis. Hepatic levels of fibrosis protein markers were significantly increased in WT-FF. The nitroxidative stress marker iNOS, but not CYP2E1, was significantly elevated only in FF-fed WT. Serum endotoxin, TLR-4 levels, and inflammatory markers were highest in WT-FF. FAS, PPAR-α, PPAR-γ, and CB1-R were markedly altered in WT-FF. Electron microscopy and immunoblot analyses showed significantly higher levels of ER stress in FF-fed WT. Indirect calorimetry showed that Cyp2e1-null-mice fed FF exhibited consistently higher total energy expenditure (TEE) than their corresponding WT. These results demonstrate that CYP2E1 is important in fast food-mediated liver fibrosis by promoting nitroxidative and ER stress, endotoxemia, inflammation, IR, and low TEE.
Assuntos
Citocromo P-450 CYP2E1/metabolismo , Inflamação/metabolismo , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Colesterol/metabolismo , Citocromo P-450 CYP2E1/genética , Estresse do Retículo Endoplasmático , Metabolismo Energético , Fast Foods , Fibrose , Humanos , Mediadores da Inflamação/sangue , Resistência à Insulina , Fígado/metabolismo , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Knockout , Estresse OxidativoRESUMO
We hypothesized that dietary walnut would prevent high-fat-diet (HFD)-induced hepatic apoptosis based on its antioxidant properties. Male C57BL/6J mice were fed a rodent chow or HFD (45% energy-derived)±walnuts (21.5% energy-derived) for 6 weeks. Liver histological and biochemical analyses revealed significantly elevated fat accumulation in mice fed HFD compared to mice fed the chow or HFD±walnuts. Walnut supplementation prevented HFD-mediated alteration of the levels of key proteins in lipid homeostasis such as Sirt1, AMPK and FAS, leading to decreased fat accumulation. In addition, walnut supplementation to HFD significantly decreased the hepatic levels of cytochrome P450-2E1, nitrated proteins and lipid peroxidation. Furthermore, walnut supplementation decreased the activated cell-death-associated p-JNK and p-p38K accompanied with increased hepatocyte apoptosis in HFD group. The beneficial effects of dietary walnut likely result, at least partially, from its antioxidant ingredients and attenuating HFD-induced hepatic steatosis, nitroxidative stress and apoptosis.
Assuntos
Apoptose , Dieta Hiperlipídica/efeitos adversos , Alimento Funcional , Juglans , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Nozes , Estresse Oxidativo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Biomarcadores/metabolismo , Citocromo P-450 CYP2E1/metabolismo , Ácido Graxo Sintases/metabolismo , Metabolismo dos Lipídeos , Peroxidação de Lipídeos , Fígado/enzimologia , Fígado/metabolismo , Fígado/patologia , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Fosforilação , Processamento de Proteína Pós-Traducional , Distribuição Aleatória , Sirtuína 1/metabolismoRESUMO
Fibroblast growth factors (FGFs) are pleiotropic growth factors that control cell proliferation, migration, and differentiation. Herein, we evaluated whether visceral adiposity of mice is accompanied by the alteration of signaling molecules mediated by fibroblast growth factor receptor 1 (FGFR1) induced by using two different male C57BL/6J mice models of obesity namely high-fat diet (HFD)-induced obesity for 12 weeks or mice with genetic deletion of leptin (ob/ob). Both HFD-fed and ob/ob mice exhibited significantly higher messenger RNA (mRNA) levels of FGF1, cyclin D (cycD), transcription factor E2F1, peroxisome proliferator-activated receptor-gamma 2 (PPAR-γ2), CCAAT-enhancer-binding protein alpha (C/EBPα), and adipocyte protein 2 (aP2) genes in their epididymal adipose tissues compared to those of the normal diet (ND)-fed and lean control mice, respectively. In addition, immunoblot analyses of the epididymal adipose tissues revealed that both mice exposed to HFD and ob/ob mice exhibited elevated phosphorylation of FGFR1, extracellular-signal-regulated kinase (ERK), and retinoblastoma (Rb) proteins. These data support the notion that FGF1-mediated signaling represents an important signaling cascade related to adipogenesis, at least partially, among other known signaling pathways. These new findings regarding the molecular mechanisms controlling adipose tissue plasticity provide a novel insight about the functional network with potential therapeutic application against obesity.
Assuntos
Tecido Adiposo Branco/metabolismo , Adiposidade , Fator 1 de Crescimento de Fibroblastos/metabolismo , Obesidade/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Regulação para Cima , Tecido Adiposo Branco/patologia , Animais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Ciclina D/genética , Ciclina D/metabolismo , Dieta Hiperlipídica/efeitos adversos , Fator de Transcrição E2F1/genética , Fator de Transcrição E2F1/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Fator 1 de Crescimento de Fibroblastos/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Obesidade/etiologia , Obesidade/patologia , Análise de Sequência com Séries de Oligonucleotídeos , PPAR gama/genética , PPAR gama/metabolismo , Fosforilação , Processamento de Proteína Pós-Traducional , RNA Mensageiro/metabolismo , Distribuição Aleatória , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genéticaRESUMO
In this study, we evaluated the protective effects of dietary walnuts on high-fat diet (HFD)-induced fatty liver and studied the underlying mechanisms. Male C57BL/6J mice were fed either a regular rodent chow or HFD (45% energy-derived) with or without walnuts (21.5% energy-derived) for 20weeks. Walnut supplementation did not change HFD-induced increase in body weight or visceral fat mass. However, dietary walnuts significantly decreased the amounts of hepatic triglyceride (TG) observed in HFD-fed mice. The addition of walnuts significantly altered the levels of proteins, involved in the hepatic lipid homeostasis, including AMP-activated protein kinase, fatty acid synthase and peroxisome proliferator-activated receptor-α. Since adipocyte inflammation and apoptosis are reportedly important in regulating hepatic fat accumulation, we also evaluated the protective effects of walnuts on adipose tissue injury. Real-time polymerase chain reaction results revealed that adipose tissues isolated from mice fed the HFD+walnut diets showed significantly decreased levels of macrophage infiltration with suppressed expression of proinflammatory genes compared to those significantly elevated in mice fed HFD alone. These improvements also coincided with reduction of HFD-induced apoptosis of adipocytes by dietary walnuts. However, the supplemented walnuts did not significantly alter HFD-induced peripheral glucose intolerance or insulin resistance despite a trend of improvement. Collectively, these results demonstrate that the protective effects of walnuts against HFD-induced hepatic TG accumulation in mice are mediated, at least partially, by modulating the key proteins in hepatic lipid homeostasis and suppression of the genes related to adipose tissue inflammation and macrophage infiltration as well as prevention of adipocyte apoptosis.
Assuntos
Tecido Adiposo/metabolismo , Dieta Hiperlipídica , Ácidos Graxos/metabolismo , Inflamação/metabolismo , Juglans , Fígado/metabolismo , Triglicerídeos/metabolismo , Tecido Adiposo/patologia , Animais , Inflamação/patologia , CamundongosRESUMO
The role of ethanol-inducible cytochrome P450-2E1 (CYP2E1) in promoting aging-dependent hepatic disease is unknown and thus was investigated in this study. Young (7 weeks) and aged female (16 months old) wild-type (WT) and Cyp2e1-null mice were used in this study to evaluate age-dependent changes in liver histology, steatosis, apoptosis, fibrosis and many nitroxidative stress parameters. Liver histology showed that aged WT mice exhibited markedly elevated hepatocyte vacuolation, ballooning degeneration, and inflammatory cell infiltration compared to all other groups. These changes were accompanied with significantly higher hepatic triglyceride and serum cholesterol in aged WT mice although serum ALT and insulin resistance were not significantly altered. Aged WT mice showed the highest rates of hepatocyte apoptosis and hepatic fibrosis. Further, the highest levels of hepatic hydrogen peroxide, lipid peroxidation, protein carbonylation, nitration, and oxidative DNA damage were observed in aged WT mice. These increases in the aged WT mice were accompanied by increased levels of mitochondrial nitroxidative stress and alteration of mitochondrial complex III and IV proteins in aged WT mice, although hepatic ATP levels seems to be unchanged. In contrast, the aging-related nitroxidative changes were very low in aged Cyp2e1-null mice. These results suggest that CYP2E1 is important in causing aging-dependent hepatic steatosis, apoptosis and fibrosis possibly through increasing nitroxidative stress and that CYP2E1 could be a potential target for translational research in preventing aging-related liver disease.
Assuntos
Envelhecimento , Apoptose , Citocromo P-450 CYP2E1/fisiologia , Fígado Gorduroso/enzimologia , Estresse Oxidativo , Animais , Fígado Gorduroso/patologia , Feminino , Hepatócitos/fisiologia , Peroxidação de Lipídeos , Camundongos da Linhagem 129 , Camundongos Knockout , Carbonilação ProteicaRESUMO
Mitochondria are important for providing cellular energy ATP through the oxidative phosphorylation pathway. They are also critical in regulating many cellular functions including the fatty acid oxidation, the metabolism of glutamate and urea, the anti-oxidant defense, and the apoptosis pathway. Mitochondria are an important source of reactive oxygen species leaked from the electron transport chain while they are susceptible to oxidative damage, leading to mitochondrial dysfunction and tissue injury. In fact, impaired mitochondrial function is commonly observed in many types of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, alcoholic dementia, brain ischemia-reperfusion related injury, and others, although many of these neurological disorders have unique etiological factors. Mitochondrial dysfunction under many pathological conditions is likely to be promoted by increased nitroxidative stress, which can stimulate post-translational modifications (PTMs) of mitochondrial proteins and/or oxidative damage to mitochondrial DNA and lipids. Furthermore, recent studies have demonstrated that various antioxidants, including naturally occurring flavonoids and polyphenols as well as synthetic compounds, can block the formation of reactive oxygen and/or nitrogen species, and thus ultimately prevent the PTMs of many proteins with improved disease conditions. Therefore, the present review is aimed to describe the recent research developments in the molecular mechanisms for mitochondrial dysfunction and tissue injury in neurodegenerative diseases and discuss translational research opportunities.