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1.
Environ Pollut ; 271: 116304, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33401208

RESUMO

Epidemiological studies have demonstrated that the general population's exposure to bisphenol A (BPA) substitutes is ubiquitous. Bisphenol F (BPF), one of the main BPA substitutes, is increasingly replacing BPA in plastics for food and beverage applications. Accumulating evidence suggests that BPA exposure is associated with nonalcoholic fatty liver disease (NAFLD)-like changes. However, the potential effects of BPF on lipid homeostasis remain poorly understood. In the present study, an epidemiological analysis with LC-MS-MS revealed that the BPF concentrations in the serum of NAFLD patients were significantly higher than those in a control group. Supporting this result, using Oil Red O, BODIPY 493/503, LipidTox Deep Red staining and gas chromatography-time-of-flight mass spectrometry (TOF-MS) assays, we found that BPF exposure induced NAFLD-like changes, with obvious lipid droplet deposition, triglyceride (TG) and fatty acids increase in mouse livers. Meanwhile, lipid droplet deposition and TG increase induced by BPF were also observed in HepG2 cells, accompanied by autophagic flux blockade, including autophagosome accumulation and the decreased degradation of SQSTM1/p62. Using adenoviruses dual-reporter plasmid RFP-GFP-LC3, RFP-GFP-PLIN2 transfection, AO staining, and EGFR degradation assays, we demonstrated that BPF treatment impaired lysosomal degradative capacity, since BPF treatment obviously impaired lysosomal acidification, manifested as decreased lysosomal hydrolase cathepsin L (CTSL) and mature cathepsin D (CTSD) in HepG2 and mouse liver issues. Additionally, v-ATPase D, a multi-subunit enzyme that mediates acidification of eukaryotic intracellular organelles, significantly decreased after BPF exposure in both the vitro and in vivo studies. This study ascertained a novel mechanism involving dysfunctional of lysosomal degradative capacity induced by BPF, which contributes to lipophagic disorders and causes lipid droplet deposition. This work provides evidence that lysosomes may be a target organelle where BPF exerts its potential toxicity; therefore, novel intervention strategies targeting lysosome are promising for BPF-induced NAFLD-like changes.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Compostos Benzidrílicos/toxicidade , Humanos , Gotículas Lipídicas , Lisossomos , Camundongos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Fenóis
2.
Am J Physiol Gastrointest Liver Physiol ; 320(2): G166-G174, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33325808

RESUMO

Human carboxylesterase 2 (CES2) has triacylglycerol hydrolase (TGH) activities and plays an important role in lipolysis. In this study, we aim to determine the role of human CES2 in the progression or reversal of steatohepatitis in diet-induced or genetically obese mice. High-fat/high-cholesterol/high-fructose (HFCF) diet-fed C57BL/6 mice or db/db mice were intravenously injected with an adeno-associated virus expressing human CES2 under the control of an albumin promoter. Human CES2 protected against HFCF diet-induced nonalcoholic fatty liver disease (NAFLD) in C57BL/6J mice and reversed steatohepatitis in db/db mice. Human CES2 also improved glucose tolerance and insulin sensitivity. Mechanistically, human CES2 reduced hepatic triglyceride (T) and free fatty acid (FFA) levels by inducing lipolysis and fatty acid oxidation and inhibiting lipogenesis via suppression of sterol regulatory element-binding protein 1. Furthermore, human CES2 overexpression improved mitochondrial respiration and glycolytic function, and inhibited gluconeogenesis, lipid peroxidation, apoptosis, and inflammation. Our data suggest that hepatocyte-specific expression of human CES2 prevents and reverses steatohepatitis. Targeting hepatic CES2 may be an attractive strategy for treatment of NAFLD.NEW & NOTEWORTHY Human CES2 attenuates high-fat/cholesterol/fructose diet-induced steatohepatitis and reverses steatohepatitis in db/db mice. Mechanistically, human CES2 induces lipolysis, fatty acid and glucose oxidation, and inhibits hepatic glucose production, inflammation, lipid oxidation, and apoptosis. Our data suggest that human CES2 may be targeted for treatment of non-alcoholic steatohepatitis (NASH).


Assuntos
Carboxilesterase/metabolismo , Hepatócitos/enzimologia , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/terapia , Ácido 3-Hidroxibutírico/sangue , Ácido 3-Hidroxibutírico/metabolismo , Alanina Transaminase/sangue , Alanina Transaminase/metabolismo , Animais , Apoptose/fisiologia , Aspartato Aminotransferases/sangue , Aspartato Aminotransferases/metabolismo , Glicemia , Carboxilesterase/genética , Dieta/efeitos adversos , Hidroxiprolina/sangue , Hidroxiprolina/metabolismo , Metabolismo dos Lipídeos , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Obesidade/induzido quimicamente , Espécies Reativas de Oxigênio/metabolismo
3.
Chem Biol Interact ; 330: 109199, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32805210

RESUMO

Obesity is characterized by the deposition of excessive body fat, and is caused by energy imbalance, especially when consuming fat-rich diets. High fat diet (HFD)-associated obesity is greatly common in patients with non-alcoholic fatty liver disease (NAFLD) that is emerging as one of the most universal causes of liver disease worldwide, especially in Western countries. In spite of its high prevalence, only a small proportion of affected individuals will become inflamed, followed by fibrosis and chronic liver diseases, and most patients only show simple steatosis. In this case, the full comprehension of the mechanisms underlying the progression of NAFLD is of extreme significance; in spite of progress in this field, awareness on the development of NAFLD is still incomplete. Traditionally, liver steatosis is commonly connected with HFD, obesity, and insulin resistance (IR). Recently, various possible mechanisms have been put forward for liver damage, including endoplasmic reticulum stress, perturbation of autophagy, mitochondrial dysfunction, hepatocellular apoptosis, gut microbiota imbalance, dysregulation of microRNAs, and genetic/epigenetic risk factors, as well as an increase in inflammatory responses, among many others. Collectively, these proposed mechanisms allow for a variety of hits acting together on subjects to mediated NAFLD and will offer a more accurate explanation for progression of NAFLD. Therefore, this review summarizes the present information concerning NAFLD after HFD exposure, as well as discusses possible mechanisms through which it may arise.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/complicações
4.
Life Sci ; 256: 118012, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32593710

RESUMO

AIMS: Bisphenol (BP)-A exposure can impair glucose and lipid metabolism. However, it is unclear whether this endocrine disruptor (ED) modulates these processes in postmenopause, a period with organic changes that increase the risk for metabolic diseases. Herein, we evaluated the effects of BPA exposure on adiposity, glucose homeostasis and hepatic steatosis in ovariectomized (OVX) mice fed on a high-fat diet (HFD). MAIN METHODS: Adult Swiss female mice were OVX and submitted to a normolipidic diet or HFD and drinking water without [control (OVX CTL) and OVX HFD groups, respectively] or with 1 µg/mL BPA (OVX CBPA and OVX HBPA groups, respectively), for 3 months. KEY FINDINGS: OVX HFD females displayed increased adiposity, glucose intolerance, insulin resistance and moderate hepatic steatosis. This effect was associated with a high hepatic expression of genes involved in lipogenesis (Srebf1 and Scd1), ß-oxidation (Cpt1a) and endoplasmic reticulum (ER) stress (Hspa5 and Hyou1). BPA did not alter adiposity or glucose homeostasis disruptions induced by HFD. However, this ED triggered severe steatosis, exacerbating hepatic fat and collagen depositions in OVX HBPA, in association with a reduction in Mttp mRNA, and up-regulation of genes involved in ß-oxidation (Acox1 and Acadvl), mitochondrial uncoupling (Ucp2), ER stress (Hyou1 and Atf6) and chronic liver injury (Tgfb1and Casp8). Furthermore, BPA caused mild steatosis in OVX CBPA females, increasing the hepatic total lipids and mRNAs for Srebf1, Scd1, Hspa5, Hyou1 and Atf6. SIGNIFICANCE: BPA aggravated hepatic steatosis in OVX mice. Especially when combined with a HFD, BPA caused NAFLD progression, which was partly mediated by chronic ER stress and the TGF-ß1 pathway.


Assuntos
Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Fenóis/toxicidade , Adiposidade/efeitos dos fármacos , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Progressão da Doença , Feminino , Glucose/metabolismo , Resistência à Insulina , Lipogênese/efeitos dos fármacos , Camundongos , Hepatopatia Gordurosa não Alcoólica/patologia , Ovariectomia
5.
Environ Res ; 188: 109824, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32593899

RESUMO

Exposure to arsenic is a risk factor for nonalcoholic steatohepatitis (NASH). Ferroptosis is a form of regulated cell death defined by the accumulation of lipid peroxidation. In the current study, we observed the occurrence of ferroptosis in arsenic-induced NASH by assessing ferroptosis related hallmarks. In vitro, we found that ferrostatin-1 effectively attenuated the executing of ferroptosis and NASH. Simultaneously, the expression of ACSL4 (acyl-CoA synthetase long-chain family member 4) was upregulated in rat's liver and L-02 cells exposed to arsenic. While, suppression of ACSL4 with rosiglitazone or ACSL4 siRNA remarkably alleviated arsenic-induced NASH and ferroptosis through diminishing 5-hydroxyeicosatetraenoic acid (5-HETE) content. Additionally, Mitofusin 2 (Mfn2), a physical tether between endoplasmic reticulum and mitochondria, has rarely been explored in the ferroptosis. Using Mfn2 siRNA or inositol-requiring enzyme 1 alpha (IRE1α) inhibitor, we found NASH and ferroptosis were obviously mitigated through reducing 5-HETE content. Importantly, Co-IP assay indicated that Mfn2 could interact with IRE1α and promoted the production of 5-HETE, ultimately led to ferroptosis and NASH. Collectively, our data showed that ferroptosis is involved in arsenic-induced NASH. These data provide insightful viewpoints into the mechanism of arsenic-induced NASH.


Assuntos
Arsênico , Hepatopatia Gordurosa não Alcoólica , Animais , Arsênico/toxicidade , Coenzima A Ligases , Endorribonucleases/efeitos dos fármacos , Endorribonucleases/fisiologia , Ferroptose , GTP Fosfo-Hidrolases/efeitos dos fármacos , GTP Fosfo-Hidrolases/fisiologia , Proteínas Mitocondriais/efeitos dos fármacos , Proteínas Mitocondriais/fisiologia , Complexos Multienzimáticos/efeitos dos fármacos , Complexos Multienzimáticos/fisiologia , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Proteínas Serina-Treonina Quinases/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/fisiologia , Ratos
6.
Toxicol Appl Pharmacol ; 398: 115009, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32353385

RESUMO

Significant attention has been given to the potential of environmental chemicals to disrupt lipid homeostasis at the cellular level. These chemicals, classified as obesogens, are abundantly used in a wide variety of consumer products. However, there is a significant lack of information regarding the mechanisms by which environmental exposure can contribute to the onset of obesity and non-alcoholic fatty liver disease (NAFLD). Several studies have described the interaction of potential obesogens with lipid-related peroxisome proliferator-activated receptors (PPAR). However, no studies have quantified the degree of modification to lipidomic profiles in relevant human models, making it difficult to directly link PPAR agonists to the onset of lipid-related diseases. A quantitative metabolomic approach was used to examine the dysregulation of lipid metabolism in human liver cells upon exposure to potential obesogenic compounds. The chemicals rosiglitazone, perfluorooctanoic acid, di-2-ethylexylphthalate, and tributyltin significantly increased total lipids in liver cells, being diglycerides, triglycerides and phosphatidylcholines the most prominent. Contrarily, perfluorooctane sulfonic acid and the pharmaceutical fenofibrate appeared to lower total lipid concentrations, especially those belonging to the acylcarnitine, ceramide, triglyceride, and phosphatidylcholine groups. Fluorescence microscopy analysis for cellular neutral lipids revealed significant lipid bioaccumulation upon exposure to obesogens at environmentally relevant concentrations. This integrated omics analysis provides unique mechanistic insight into the potential of these environmental pollutants to promote diseases like obesity and NAFLD. Furthermore, this study provides a significant contribution to advance the understanding of molecular signatures related to obesogenic chemicals and to the development of alternatives to in vivo experimentation.


Assuntos
Exposição Ambiental/efeitos adversos , Poluentes Ambientais/efeitos adversos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Obesidade/induzido quimicamente , Obesidade/metabolismo , Linhagem Celular , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Homeostase/efeitos dos fármacos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolômica/métodos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/metabolismo , PPAR gama/metabolismo
7.
PLoS One ; 15(5): e0232630, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32357187

RESUMO

Inflammation plays an essential role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Berberine (BBR), an isoquinoline alkaloid isolated from Chinese medicinal herbs, has been widely used to treat various diseases, including liver diseases for hundreds of years. The previous studies have shown that BBR inhibits high fat-diet-induced steatosis and inflammation in rodent models of NAFLD. However, the underlying molecular mechanisms remain unclear. This study is aimed to identify the potential mechanisms by which BBR inhibits free fatty acid (FFA) and LPS-induced inflammatory response in mouse macrophages and hepatocytes. Mouse RAW264.7 macrophages and primary mouse hepatocytes were treated with palmitic acid (PA) or LPS or both with or without BBR (0-10 µM) for different periods (0-24 h). The mRNA and protein levels of proinflammatory cytokines (TNF-α, IL-6, IL-1ß, MCP-1) and ER stress genes (CHOP, ATF4, XBP-1) were detected by real-time RT-PCR, Western blot and ELISA, respectively. The results indicated that BBR significantly inhibited PA and LPS-induced activation of ER stress and expression of proinflammatory cytokines in macrophages and hepatocytes. PA/LPS-mediated activation of ERK1/2 was inhibited by BBR in a dose-dependent manner. In summary, BBR inhibits PA/LPS-induced inflammatory responses through modulating ER stress-mediated ERK1/2 activation in macrophages and hepatocytes.


Assuntos
Berberina/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Berberina/uso terapêutico , Citocinas/metabolismo , Inflamação/induzido quimicamente , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Ácido Palmítico/toxicidade , Células RAW 264.7
8.
Sci Rep ; 10(1): 6689, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32317687

RESUMO

Sugar-sweetened beverage consumption is a known independent risk factor for nonalcoholic steatohepatitis (NASH). Non-caloric sweeteners (NCS) are food additives providing sweetness without calories and are considered safe and/or not metabolized by the liver. The potential role of newer NCS in the regulation of NASH, however, remain unknown. Our study aimed to determine the impact of newer NCS including Rebaudioside A and sucralose on NASH using high fat diet induced obesity mouse model by substituting fructose and sucrose with NCS in the drinking water. We characterized the phenotype of NCS- treated obesity and investigated the alterations of hepatic function and underlying mechanisms. We found that NCS have no impact on weight gain and energy balance in high fat diet induced obesity. However, in comparison to fructose and sucrose, Rebaudioside A significantly improved liver enzymes, hepatic steatosis and hepatic fibrosis. Additionally, Rebaudioside A improved endoplasmic reticulum (ER) stress related gene expressions, fasting glucose levels, insulin sensitivity and restored pancreatic islet cell mass, neuronal innervation and microbiome composition. We concluded that Rebaudioside A significantly ameliorated murine NASH, while the underlying mechanisms requires further investigation.


Assuntos
Diterpenos de Caurano/uso terapêutico , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Bebidas Adoçadas com Açúcar/efeitos adversos , Adiposidade/efeitos dos fármacos , Animais , Dieta Hiperlipídica , Diterpenos de Caurano/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Frutose , Glucose/metabolismo , Homeostase/efeitos dos fármacos , Resistência à Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/patologia , Fígado/efeitos dos fármacos , Fígado/fisiopatologia , Camundongos , Microbiota/efeitos dos fármacos , Obesidade/etiologia , Obesidade/metabolismo , Substâncias Protetoras/farmacologia , Ganho de Peso/efeitos dos fármacos
9.
J Agric Food Chem ; 68(14): 4215-4226, 2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32181656

RESUMO

Ginsenoside Rg2 has been previously reported to reduce glucose production and adipogenesis in adipose tissue. However, the effects of ginsenosides Rg2 on hepatic lipid metabolism remain vacant. In this study, we found that ginsenoside Rg2 treatment significantly attenuated oleic acid and palmitic acid (OA&PA)-induced intracellular lipid deposition and oxidative stress in mouse primary hepatocytes. C57BL/6J mice that are fed with a high-fat diet (HFD) and treated with ginsenosides Rg2 displayed decreased body weight, reversed hepatic steatosis, and improved glucose tolerance and insulin sensitivity. Ginsenoside Rg2 administration significantly ameliorated HFD-induced hepatic oxidative stress and apoptosis. Moreover, Ginsenoside Rg2 had a good affinity with Sirtuin1 (SIRT1) and regulated its expression in vivo and in vitro. Deficiency of SIRT1 eliminated the therapeutic effect of ginsenoside Rg2 on lipid accumulation and overproduction of reactive oxygen species (ROS) in OA&PA-induced mice primary hepatocytes. Ginsenoside Rg2 treatment failed to alter the lipid and glucose disorder in hepatic SIRT1 deficient mice feeding on HFD. SIRT1 deficiency dissolves the therapeutic effect of ginsenoside Rg2 on oxidative stress and hepatocyte apoptosis induced by HFD. In summary, ginsenoside Rg2 plays a therapeutic role in HFD-induced hepatosteatosis of mice by decreasing the lipogenesis process and improving antioxidant capacity in an SIRT1-dependent manner.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Ginsenosídeos/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Sirtuína 1/metabolismo , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Fígado , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Ácido Oleico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ácido Palmítico/metabolismo
10.
Environ Int ; 138: 105648, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32187572

RESUMO

Microcystins (MCs) produced by cyanobacteria pose serious threats to human health. However, the contribution of long-term exposure to MCs to the development of nonalcoholic fatty liver disease (NAFLD) remains poorly documented. In this study, we estimated the environmental uptake of MCs by a small population of fishers who have lived for many years on Meiliang Bay of Lake Taihu, where cyanobacterial blooms occur frequently. Serum biochemical indices of liver function and their relationships with MC contamination in these people were also investigated. Moreover, to mimic the long-term effects of MC on the livers of fishers, an animal model was established in which mice were exposed to MC-LR at an environmentally relevant level, a reference level (the no-observed adverse effect level, NOAEL), and three times the NOAEL through drinking water for 12 months. We estimated the total daily intake of MCs by fishers through contaminated lake water and food to be 5.95 µg MC-LReq, far exceeding the tolerable daily intake (2.40 µg MC-LReq) proposed by the World Health Organization (WHO). More than 80% of participants had at least one abnormal serum marker. The indices of aspartate aminotransferase (AST)/alanine aminotransferase (ALT), triglyceride (TG), globulin (GLB), and lactate dehydrogenase (LDH) had close positive associations with MC contamination, indicating that both liver damage and lipid metabolism dysfunction were induced by chronic MC exposure. Furthermore, the animal experimental results showed that long-term exposure to MC-LR at the environmentally relevant level led to hepatic steatosis with molecular alterations in circadian rhythm regulation, lipid metabolic processes, and the cell cycle pathway. Exposure to MC-LR at or above the NOAEL worsened the pathological phenotype towards nonalcoholic steatohepatitis disease (NASH) or fibrosis. These results suggest that prolonged exposure to the reference level (NOAEL) of MC-LR could cause severe liver injury to mammals. People with long-term environmental exposure to MCs might be at high risk for developing NAFLD.


Assuntos
Cianobactérias , Hepatopatia Gordurosa não Alcoólica , Animais , Modelos Animais de Doenças , Exposição Ambiental/efeitos adversos , Humanos , Fígado/química , Camundongos , Microcistinas/análise , Microcistinas/toxicidade , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente
12.
Nutrients ; 12(1)2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31936026

RESUMO

The laboratory mouse is the most common used mammalian research model in biomedical research. Usually these animals are maintained in germ-free, gnotobiotic, or specific-pathogen-free facilities. In these facilities, skilled staff takes care of the animals and scientists usually don't pay much attention about the formulation and quality of diets the animals receive during normal breeding and keeping. However, mice have specific nutritional requirements that must be met to guarantee their potential to grow, reproduce and to respond to pathogens or diverse environmental stress situations evoked by handling and experimental interventions. Nowadays, mouse diets for research purposes are commercially manufactured in an industrial process, in which the safety of food products is addressed through the analysis and control of all biological and chemical materials used for the different diet formulations. Similar to human food, mouse diets must be prepared under good sanitary conditions and truthfully labeled to provide information of all ingredients. This is mandatory to guarantee reproducibility of animal studies. In this review, we summarize some information on mice research diets and general aspects of mouse nutrition including nutrient requirements of mice, leading manufacturers of diets, origin of nutrient compounds, and processing of feedstuffs for mice including dietary coloring, autoclaving and irradiation. Furthermore, we provide some critical views on the potential pitfalls that might result from faulty comparisons of grain-based diets with purified diets in the research data production resulting from confounding nutritional factors.


Assuntos
Ração Animal/análise , Dieta/veterinária , Gorduras na Dieta/administração & dosagem , Ciência dos Animais de Laboratório , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Fenômenos Fisiológicos da Nutrição Animal , Animais , Camundongos
13.
Mar Drugs ; 18(1)2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31963560

RESUMO

The Asian coastal communities have used the brown seaweeds Fucus vesiculosus and Ascophyllum nodosum since ancient times. Recently, some in vitro and in vivo studies have demonstrated their abilities in reducing risk factors for metabolic syndrome. Here, we analyzed the protective effect of a phytocomplex extracted from these seaweeds on the deposition of fat in the liver after the administration of a high-fat diet (HFD) to rats for five weeks. The administration of F. vesiculosus and A. nodosum led to significant reductions in microvescicular steatosis and plasma biochemical and lipid parameters, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total and conjugated bilirubin, and triglycerides. Furthermore, the postprandial glycemic peak was delayed and significantly reduced (p < 0.01) by the algal extract administration. In conclusion, this extract is effective in reducing microvescicular steatosis and improving glycemic control, thereby lowering the risk of nonalcoholic fatty liver disease, obesity, and diabetes, diseases related to the consumption of fat and sugar-enriched diets.


Assuntos
Ascophyllum/química , Dieta Redutora/efeitos adversos , Fucus/química , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Extratos Vegetais/farmacologia , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Glicemia/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Fígado/metabolismo , Masculino , Hepatopatia Gordurosa não Alcoólica/metabolismo , Período Pós-Prandial/efeitos dos fármacos , Ratos , Ratos Wistar , Alga Marinha/química , Triglicerídeos/metabolismo
14.
Chemosphere ; 239: 124747, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31514003

RESUMO

BACKGROUNDS: Polychlorinated biphenyls are persistent environmental pollutants associated with the onset of non-alcoholic fatty liver disease in humans, but there is limited information on the underlying mechanism. In the present study, we investigated the alterations in gene expression profiles in normal human liver cells L-02 following exposure to 2, 3, 3', 4, 4', 5 - hexachlorobiphenyl (PCB 156), a potent compound that may induce non-alcoholic fatty liver disease. METHODS: The L-02 cells were exposed to PCB 156 for 72 h and the contents of intracellular triacylglyceride and total cholesterol were subsequently measured. Microarray analysis of mRNAs and long non-coding RNAs (lncRNAs) in the cells was also performed after 3.4 µM PCB 156 treatment. RESULTS: Exposure to PCB 156 (3.4 µM, 72 h) resulted in significant increases of triacylglyceride and total cholesterol concentrations in L-02 cells. Microarray analysis identified 222 differentially expressed mRNAs and 628 differentially expressed lncRNAs. Gene Ontology and pathway analyses associated the differentially expressed mRNAs with metabolic and inflammatory processes. Moreover, lncRNA-mRNA co-expression network revealed 36 network pairs comprising 10 differentially expressed mRNAs and 34 dysregulated lncRNAs. The results of bioinformatics analysis further indicated that dysregulated lncRNA NONHSAT174696, lncRNA NONHSAT179219, and lncRNA NONHSAT161887, as the regulators of EDAR, CYP1B1, and ALDH3A1 respectively, played an important role in the PCB 156-induced lipid metabolism disorder. CONCLUSION: Our findings provide an overview of differentially expressed mRNAs and lncRNAs in L-02 cells exposed to PCB 156, and contribute to the field of polychlorinated biphenyl-induced non-alcoholic fatty liver disease.


Assuntos
Fígado/efeitos dos fármacos , Bifenilos Policlorados/toxicidade , Transcriptoma/efeitos dos fármacos , Aldeído Desidrogenase/genética , Linhagem Celular , Colesterol/metabolismo , Citocromo P-450 CYP1B1/genética , Receptor Edar/genética , Perfilação da Expressão Gênica , Humanos , Fígado/citologia , Fígado/fisiologia , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/patologia , Análise de Sequência com Séries de Oligonucleotídeos , RNA Longo não Codificante , RNA Mensageiro/metabolismo , Testes de Toxicidade , Triglicerídeos/metabolismo
15.
Redox Biol ; 28: 101314, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31514051

RESUMO

Nuclear factor-erythroid 2 related factor 2 (Nrf2)-mediated signaling plays a central role in maintaining cellular redox homeostasis of hepatic cells. Carbon monoxide releasing molecule-A1 (CORM-A1) has been reported to stimulate up-regulation and nuclear translocation of Nrf2 in hepatocytes. However, the role of CORM-A1 in improving lipid metabolism, antioxidant signaling and mitochondrial functions in nonalcoholic steatohepatitis (NASH) is unknown. In this study, we report that CORM-A1 prevents hepatic steatosis in high fat high fructose (HFHF) diet fed C57BL/6J mice, used as model of NASH. The beneficial effects of CORM-A1 in HFHF fed mice was associated with improved lipid homeostasis, Nrf2 activation, upregulation of antioxidant responsive (ARE) genes and increased ATP production. As, mitochondria are intracellular source of reactive oxygen species (ROS) and important sites of lipid metabolism, we further investigated the mechanisms of action of CORM-A1-mediated improvement in mitochondrial function in palmitic acid (PA) treated HepG2 cells. Cellular oxidative stress and cell viability were found to be improved in PA + CORM-A1 treated cells via Nrf2 translocation and activation of cytoprotective genes. Furthermore, in PA treated cells, CORM-A1 improved mitochondrial oxidative stress, membrane potential and rescued mitochondrial biogenesis thru upregulation of Drp1, TFAM, PGC-1α and NRF-1 genes. CORM-A1 treatment improved cellular status by lowering glycolytic respiration and maximizing OCR. Improvement in mitochondrial respiration and increment in ATP production in PA + CORM-A1 treated cells further corroborate our findings. In summary, our data demonstrate for the first time that CORM-A1 ameliorates tissue damage in steatotic liver via Nrf2 activation and improved mitochondrial function, thus, suggesting the anti-NASH potential of CORM-A1.


Assuntos
Boranos/administração & dosagem , Carbonatos/administração & dosagem , Dieta Hiperlipídica/efeitos adversos , Xarope de Milho Rico em Frutose/efeitos adversos , Fator 2 Relacionado a NF-E2/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Boranos/farmacologia , Carbonatos/farmacologia , Sobrevivência Celular , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ácido Palmítico/farmacologia , Transdução de Sinais/efeitos dos fármacos
17.
Cell Mol Life Sci ; 77(9): 1709-1719, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31713637

RESUMO

Hereditary fructose intolerance (HFI) is a rare inborn disease characterized by a deficiency in aldolase B, which catalyzes the cleavage of fructose 1,6-bisphosphate and fructose 1-phosphate (Fru 1P) to triose molecules. In patients with HFI, ingestion of fructose results in accumulation of Fru 1P and depletion of ATP, which are believed to cause symptoms, such as nausea, vomiting, hypoglycemia, and liver and kidney failure. These sequelae can be prevented by a fructose-restricted diet. Recent studies in aldolase B-deficient mice and HFI patients have provided more insight into the pathogenesis of HFI, in particular the liver phenotype. Both aldolase B-deficient mice (fed a very low fructose diet) and HFI patients (treated with a fructose-restricted diet) displayed greater intrahepatic fat content when compared to controls. The liver phenotype in aldolase B-deficient mice was prevented by reduction in intrahepatic Fru 1P concentrations by crossing these mice with mice deficient for ketohexokinase, the enzyme that catalyzes the synthesis of Fru 1P. These new findings not only provide a potential novel treatment for HFI, but lend insight into the pathogenesis of fructose-induced non-alcoholic fatty liver disease (NAFLD), which has raised to epidemic proportions in Western society. This narrative review summarizes the most recent advances in the pathogenesis of HFI and discusses the implications for the understanding and treatment of fructose-induced NAFLD.


Assuntos
Intolerância à Frutose/patologia , Frutose/efeitos adversos , Predisposição Genética para Doença , Hepatopatia Gordurosa não Alcoólica/patologia , Animais , Frutose/metabolismo , Intolerância à Frutose/tratamento farmacológico , Intolerância à Frutose/etiologia , Humanos , Camundongos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico
18.
Environ Res ; 181: 108909, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31776016

RESUMO

Polychlorinated biphenyls (PCBs) are persistent organic pollutants found in various environmental media, and there is growing evidence that PCBs may contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). The purposes of this study were to investigate whether environmental level of Aroclor 1254 (a commercial mixture of PCBs) exposure to adolescent male mice could induce the development of NAFLD and the mechanisms involved. Twenty-one-day-old male C57BL/6 mice were exposed to Aroclor 1254 (0.5-500 µg/kg body weight) by oral gavage once every third day for 60 days. The results showed that exposure to Aroclor 1254 increased body weight and decreased the liver-somatic index in a dose-dependent manner. Aroclor 1254 administration increased lipid accumulation in the liver and induced the mRNA expression of genes associated with lipogenesis, including acetyl-CoA carboxylase 1 (Acc1), acetyl-CoA carboxylase 2 (Acc2) and fatty acid synthase (Fasn). Moreover, Aroclor 1254 decreased peroxisome proliferator-activated receptor alpha (PPARα) signaling and lipid oxidation. In addition, we found that Aroclor 1254 administration induced oxidative stress in mouse liver and elevated the protein level of cyclooxygenase 2 (COX-2), an inflammatory molecule, possibly via the endoplasmic reticulum (ER) stress inositol-requiring enzyme 1α-X-box-binding protein-1 (IRE1α-XBP1) pathway, but not the nuclear factor-κB (NF-κB) pathway. In summary, adolescent exposure to environmental level of PCBs stimulated oxidative stress, ER stress and the inflammatory response and caused NAFLD in male mice. This work provides new insight into the idea that adolescent exposure to environmental level of PCBs might induce the development of NAFLD under the regulation of ER stress in males.


Assuntos
Poluentes Ambientais/toxicidade , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Bifenilos Policlorados/toxicidade , Animais , Endorribonucleases , Fígado , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Serina-Treonina Quinases
19.
Phytomedicine ; 66: 153135, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31790895

RESUMO

BACKGROUND: Gut microbiota is increasingly recognized as the key participant in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) by translocation of its products, such as lipopolysaccharide (LPS), via the dysfunctional intestinal barrier. Qushi Huayu decoction (QHD), a traditional Chinese medicine, is developed specially for NAFLD and used in clinic in China for more than a decade and previously found to ameliorate non-alcoholic steatohepatitis (NASH) induced by high-fat diet (HFD) in mice accompanied with inhibited metabolic endotoxemia and hepatic LPS signalling. PURPOSE: To investigate the mechanism of LPS gut-leakage inhibition by QHD in NASH. METHODS: Effects of QHD on gut microbioa and intestinal barrier were evaluated in NASH induced by HFD in mice. 16S rRNA sequencing is employed to analyse the gut microbiota composition. To identify the potential signalling pathway responsible for tight junction regulation, the colonic phosphoprotein profile is screened via the Phospho Explorer Antibody Array and verified in NASH, intestinal barrier dysfunctional mouse and Caco-2 cells. RESULTS: QHD ameliorates NASH accompanied with regulating the gut microbiota composition, protecting intestinal tight junctions and inhibiting LPS gut-leakage without decreasing the abundance of identified Gram-negative bacteria. The validated data of phosphorylated proteins suggested that mitogen-activated protein kinase (MAPK) pathway is predominantly responsible for the colonic tight junction regulation by QHD. CONCLUSION: QHD inhibits LPS gut-leakage in NASH, which is associated with downregulation of intestinal MAPK pathway.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Medicamentos de Ervas Chinesas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Células CACO-2 , China , Colo/metabolismo , Humanos , Intestinos/enzimologia , Lipopolissacarídeos/administração & dosagem , Masculino , Medicina Tradicional Chinesa , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Junções Íntimas/metabolismo
20.
Am J Physiol Endocrinol Metab ; 318(2): E131-E144, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31821039

RESUMO

We reported previously that increased acid sphingomyelinase (ASMase)-catalyzed hydrolysis of sphingomyelin, which leads to increases in ceramide and sphingosine 1 phosphate (S1P), played a key role in the synergistic upregulation of proinflammatory cytokines by palmitic acid (PA), a major saturated fatty acid, and lipopolysaccharide (LPS) in macrophages. Since macrophages are vital players in nonalcoholic steatohepatitis (NASH) and atherosclerosis, we assessed the effect of ASMase inhibition on NASH and atherosclerosis cooperatively induced by high-PA-containing high-fat diet (HP-HFD) and LPS in LDL receptor-deficient (LDLR-/-) mice. LDLR-/- mice were fed HP-HFD, injected with low dose of LPS and treated with or without the ASMase inhibitor amitriptyline. The neutral sphingomyelinase inhibitor GW4869 was used as control. Metabolic study showed that both amitriptyline and GW4869 reduced glucose, lipids, and insulin resistance. Histological analysis and Oil Red O staining showed that amitriptyline robustly reduced hepatic steatosis while GW4869 had modest effects. Interestingly, immunohistochemical study showed that amitriptyline, but not GW4869, strongly reduced hepatic inflammation. Furthermore, results showed that both amitriptyline and GW4869 attenuated atherosclerosis. To elucidate the underlying mechanisms whereby amitriptyline inhibited both NASH and atherosclerosis, but GW4869 only inhibited atherosclerosis, we found that amitriptyline, but not GW4869, downregulated proinflammatory cytokines in macrophages. Finally, we found that inhibition of sphingosine 1 phosphate production is a potential mechanism whereby amitriptyline inhibited proinflammatory cytokines. Collectively, this study showed that amitriptyline inhibited NASH and atherosclerosis through modulation of sphingolipid metabolism in LDLR-/- mice, indicating that sphingolipid metabolism in macrophages plays a crucial role in the linkage of NASH and atherosclerosis.


Assuntos
Amitriptilina/farmacologia , Amitriptilina/uso terapêutico , Aterosclerose/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Esfingolipídeos/metabolismo , Esfingomielina Fosfodiesterase/antagonistas & inibidores , Compostos de Anilina/farmacologia , Animais , Aterosclerose/induzido quimicamente , Aterosclerose/metabolismo , Compostos de Benzilideno/farmacologia , Glicemia/metabolismo , Citocinas/biossíntese , Dieta Hiperlipídica , Regulação para Baixo , Resistência à Insulina , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores de LDL/deficiência , Receptores de LDL/genética
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