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1.
Life Sci ; 257: 118118, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32702445

RESUMO

AIMS: Recent findings have instituted the role of hyperglycemia-related AGE/RAGE and NF-κB in instigating reactive oxygen species (ROS) mediated mitochondrial dysfunction and apoptosis of hepatocyte, which leads to steatohepatitis. Naringin, a flavanone glycoside found to possess myriads of pharmacological benefits along with its antioxidant and anti-inflammatory properties. Consequently, we aimed to decipher the effect of naringin on RAGE/NF-κB mediated mitochondrial apoptosis in type 2 diabetes mellitus (T2DM)-induced steatohepatitis. MAIN METHODS: Hepatic HepG2 cells were cultured in palmitic acid medium with and without naringin. Lipid content was examined by Oil Red O and Nile Red staining. Cellular apoptosis was determined by Annexin V-FITC/PI staining. An experimental T2DM-induced steatohepatitis was developed in Sprague Dawley rats by high-fat diet (HFD) for 12 weeks. The naringin was administrated orally at a dose of 100 mg/kg, daily for eight weeks. Glucose and insulin tolerance test was performed. Liver sections were stained by hematoxylin-eosin and picrosirius red. The mRNA and protein expression of RAGE and NF-κB were determined by qPCR, Immunofluorescence, and Immunoblotting. Mitochondrial membrane potential (MMP), cellular and mitochondrial ROS were measured by FACS. KEY FINDINGS: Palmitic acid encountered HepG2 cells and HFD fed rats exhibited hyperlipidemia, insulin resistance, abnormal aminotransferases, steatosis, and fibrosis. Besides, the level of AGEs, RAGE, NF-κB, and oxidative stress were exacerbated. Moreover, MMP, cellular and mitochondrial ROS were altered in diabetic rats. Nevertheless, the naringin treatment ameliorated the steatohepatitis by improving the levels of aforementioned parameters. SIGNIFICANCE: Collectively, these findings suggested anti-steatohepatitis potential of naringin in diabetics.


Assuntos
Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Diabetes Mellitus Tipo 2/complicações , Fígado Gorduroso/tratamento farmacológico , Flavanonas/uso terapêutico , Mitocôndrias/efeitos dos fármacos , NF-kappa B/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Animais , Diabetes Mellitus Experimental/complicações , Fígado Gorduroso/etiologia , Fígado Gorduroso/patologia , Imunofluorescência , Teste de Tolerância a Glucose , Células Hep G2/efeitos dos fármacos , Humanos , Insulina/sangue , Fígado/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
3.
Toxicol Appl Pharmacol ; 396: 114997, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32259528

RESUMO

High-fat high-fructose diet (HFF) in obesity can induce dyslipidemia and lipid accumulation both in kidney and liver which related to insulin resistance and lipotoxicity-induced cellular damage. We investigated whether dapagliflozin with or without atorvastatin could improve lipid accumulation-induced kidney and liver injury in HFF-induced insulin resistant rats. Male Wistar rats were fed with HFF for 16 weeks and then received drug treatments for 4 weeks; vehicle, dapagliflozin, atorvastatin and dapagliflozin plus atorvastatin treatment groups. HFF rats demonstrated insulin resistance, dyslipidemia, liver injury and renal dysfunction associated with impaired renal lipid metabolism and lipid accumulation. Dapagliflozin and combination treatment could improve HFF-induced insulin resistance, lipogenesis and lipotoxicity-related renal oxidative stress, inflammation, fibrosis and apoptosis leading to kidney dysfunction recovery. Liver injury-associated inflammation was also improved by these two regimens. Notably, the reduced lipid accumulation in liver and kidney that linked to an improvement of lipid oxidation was prominent in the combination treatment. Therefore, dapagliflozin combined with atorvastatin treatment exert the beneficial effects on lipid metabolism and lipotoxicity in liver and kidney injury via the attenuation of oxidative stress, fibrosis and apoptosis in insulin resistant model.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Atorvastatina/uso terapêutico , Compostos Benzidrílicos/uso terapêutico , Carboidratos da Dieta/efeitos adversos , Gorduras na Dieta/efeitos adversos , Fígado Gorduroso/tratamento farmacológico , Frutose/efeitos adversos , Glucosídeos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Resistência à Insulina , Animais , Atorvastatina/administração & dosagem , Compostos Benzidrílicos/administração & dosagem , Western Blotting , Carboidratos da Dieta/farmacologia , Quimioterapia Combinada , Frutose/farmacologia , Glucosídeos/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Masculino , Ratos , Ratos Wistar
4.
Med Sci Monit ; 26: e921905, 2020 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-32245940

RESUMO

BACKGROUND Type 2 diabetes mellitus (T2DM) and its comorbidities, including obesity, hypertension, and hyperlipidemia, are commonly associated with non-alcoholic fatty liver disease (NAFLD). Ganoderma lucidum polysaccharide (GDLP) is one of the central bioactive components in Ganoderma lucidum with anti-inflammatory, antioxidant, and hepatoprotective properties. However, the effect and mechanisms of GDLP in hepatic steatosis remain largely unknown. In the present study, we aimed to investigate the function of GDLP in hepatic steatosis and the underlying mechanism. MATERIAL AND METHODS In this study, male db/db mice were received with a high-fat diet (HFD) to investigate the effect of GDLP in T2DM-induced hepatic steatosis. The biological characteristics of the hepatic steatosis were evaluated through the detection of clinical indicators, including biochemical parameters, histopathology, and related cytokine levels. Additionally, the protein expression levels of Nrf2 (nuclear factor E2 (erythroid-derived 2)-related factor-2) signaling pathway were investigated by using western blotting and immunohistochemical staining. RESULTS The levels of food/water intake, body weight, fasting blood glucose, plasma lipids, urinary biomarkers, hepatic lipid accumulation, and tumor necrosis factor (TNF)-alpha were observably decreased in GDLP-treated db/db mice. Additionally, administration of GDLP increased the expression of various antioxidases, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), whereas it reduced the level of malonaldehyde (MDA). Furthermore, GDLP was significantly promoted protein expression level of Nrf2 and its downstream target gene HO-1 (heme oxygenase-1) while decreased TNF-alpha expression. CONCLUSIONS These results indicate that GDLP against T2DM-induced hepatic steatosis, oxidative stress, and inflammation by improving the Nrf2/HO-1 signaling pathway in db/db mice, suggesting the GDLP may serve as an effective strategy for in fatty liver treatment.


Assuntos
Fígado Gorduroso/tratamento farmacológico , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Reishi/química , Animais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Masculino , Camundongos , Polissacarídeos
5.
Curr Pharm Biotechnol ; 21(11): 1099-1106, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32188382

RESUMO

BACKGROUND: Chlorogenic Acid (CA) has diverse, recognized health effects. OBJECTIVE: This study aimed to explore the effects of CA on fat reduction and the underlying mechanism of these effects. MATERIALS AND METHODS: First, we established a Monosodium Glutamate (MSG)-induced obesity mouse model and subjected the mice to 4 weeks of CA gavage. Then, we established an oleic acidinduced model of human fatty liver in HepG2 cells, and administered a CA intervention to the cells for 48 h. Finally, we used Oil red O staining, biochemical detection kits, RT-PCR and Western blot analysis to evaluate the effects of CA on fat reduction and on related pathways. RESULTS: The CA treatment could reduce fat accumulation in the liver and reduce blood lipid levels. In addition, CA decreased the mRNA and protein levels of peroxisome proliferator-activated receptor gamma, coactivator 1 α (PGC-1α) and Uncoupling Protein 1 (UCP1) in the MSG-induced obesity mouse model and the oleic acid-induced HepG2 cells. CONCLUSION: Based on the above results, we deduced that CA could reduce body weight and fat deposition in vitro and in vivo and that the mechanism may be related to the PGC-1α/UCP-1 pathway. CA can be developed as a drug to lower blood lipids and to treat obesity.


Assuntos
Fármacos Antiobesidade/farmacologia , Ácido Clorogênico/farmacologia , Fígado Gorduroso/tratamento farmacológico , Fígado/efeitos dos fármacos , Obesidade/tratamento farmacológico , Perda de Peso/efeitos dos fármacos , Animais , Fármacos Antiobesidade/uso terapêutico , Ácido Clorogênico/uso terapêutico , Modelos Animais de Doenças , Fígado Gorduroso/metabolismo , Células Hep G2 , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Glutamato de Sódio/metabolismo , Proteína Desacopladora 1/metabolismo
6.
Mol Pharmacol ; 97(5): 314-323, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32098797

RESUMO

Farnesoid X receptor (FXR), or NR1H4, protects the liver from insults of various etiologies. A role of FXR in drug-induced liver injury has also been hypothesized yet only marginally investigated. The aim of this study was to assess the effect of FXR activation on gene expression and phenotype of the liver of mice treated with valproic acid (VPA), or 2-propylpentanoic acid, a prototypical hepatotoxic drug. Obeticholic acid (OCA) was used to activate FXR both in mice and in human hepatocellular carcinoma (Huh-7) cells. Next-generation sequencing of mouse liver tissues was performed from control, VPA, and VPA + OCA-treated mice. Pathway analysis validation was performed using real-time reverse-transcription polymerase chain reaction, Western blotting, immunohistochemistry, and fluorometric assays. FXR activation induced antioxidative pathways, which was confirmed by a marked reduction in VPA-induced lipid peroxidation and endoplasmic reticulum stress. In vitro, VPA-induced oxidative stress was independent of lipid accumulation, stemmed from the cytoplasm, and was mitigated by OCA. In the liver of the mice treated with OCA, the levels of cytochrome P450 potentially involved in VPA metabolism were increased. The hepatic lipid-lowering effect observed in animals cotreated with VPA and OCA in comparison with that of animals treated with VPA was associated with regulation of the genes involved in the steatogenic nuclear receptor peroxisome proliferator-activated γ (PPARγ) pathway. In conclusion, pronounced antioxidant activity, repression of the PPARγ pathway, and higher expression of P450 enzymes involved in VPA metabolism may underlie the hepatoprotective of FXR activation during VPA treatment. SIGNIFICANCE STATEMENT: Valproic acid-induced oxidative stress occurs in absence of lipid accumulation and is not of mitochondrial origin. Valproic acid exposure induces the expression of the steatogenic nuclear receptor peroxisome proliferator-activated γ (PPARγ) and its downstream target genes. Constitutive activation of the farnesoid X receptor (FXR) reduces PPARγ hepatic expression and induces hepatic antioxidant activity. The variability in FXR expression level/activity, for instance in individuals carrying loss-of-function genetic variants of the FXR gene, could contribute to valproic acid pharmacokinetic and toxicokinetic profile.


Assuntos
Ácido Quenodesoxicólico/análogos & derivados , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/patologia , Estresse Oxidativo , Ácido Valproico/efeitos adversos , Animais , Antioxidantes/farmacologia , Peso Corporal/efeitos dos fármacos , Linhagem Celular Tumoral , Ácido Quenodesoxicólico/farmacologia , Ácido Quenodesoxicólico/uso terapêutico , Sistema Enzimático do Citocromo P-450/metabolismo , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/fisiopatologia , Feminino , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Fígado/fisiopatologia , Testes de Função Hepática , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Transcriptoma/genética
7.
Mol Med Rep ; 21(3): 1059-1070, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32016448

RESUMO

Obesity has been increasing globally for over three decades. According to previous studies, dietary obesity is usually associated with endoplasmic reticulum stress (ERS) and STAT3 signaling, which result in interference with the homeostatic control of energy and lipid metabolism. Ginsenosides (GS) administered to mice will modulate adiposity and food intake; however, the mechanism of food inhibition is unknown. The aim of the present study was to investigate whether GS may inhibit ERS and regulate STAT3 phosphorylation in GT1­7 cells (a mouse hypothalamus gonadotropin­releasing hormone neuron cell line) and the hypothalamus in order to reduce the body weight and ameliorate hepatic steatosis in high fat diet (HFD)­induced obese mice. In the present study, GS inhibited the appetite, reduced the body weight, visceral fat, body fat content and blood glucose, and ameliorated the glucose tolerance of the obese mice compared with HFD mice. In addition, the levels of aspartate aminotransferase and alanine aminotransferase, triglyceride (TG), leptin and insulin in the serum were reduced compared with HFD mice. There was less TG in the liver, but more in the feces compared with HFD mice. Using hematoxylin and eosin staining of HepG2 cells and liver tissues, GS were demonstrated to improve the non­alcoholic fatty liver of the HFD­induced obese mice and reduce the diameter of the fat cells compared with HFD mice. GS also increased oxygen consumption and carbon dioxide emissions in the metabolic cage data compared with HFD mice. In the GT1­7 cells, GS alleviated the ERS induced by tunicamycin and enhanced the activation of the STAT3 phosphorylation pathway. Furthermore the ERS of the liver was relieved to achieve the aforementioned pharmacological effects. GS were used in the homeostatic control of the energy and lipid metabolism of a diet­induced obesity model. In conclusion, present studies suggest that GS exert these effects by increasing STAT3 phosphorylation expression and reducing the ERS. Thus, GS reduce body weight and ameliorate hepatic steatosis in HFD­induced obese mice.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fígado Gorduroso/tratamento farmacológico , Ginsenosídeos/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Obesidade/tratamento farmacológico , Fator de Transcrição STAT3/metabolismo , Adiposidade/efeitos dos fármacos , Animais , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Fígado Gorduroso/induzido quimicamente , Insulina/metabolismo , Leptina/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Fator de Transcrição STAT3/genética , Transdução de Sinais/efeitos dos fármacos
8.
J Toxicol Sci ; 45(2): 87-94, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32062620

RESUMO

Mice lacking the farnesoid X receptor (FXR) are used as a genetic model for nonalcoholic fatty liver disease because their livers exhibit hepatic steatosis and inflammation. The influence of taurine drinking on disrupted hepatic function was investigated using female Fxr-null mice. Significant decreases in the levels of hepatic damage-associated diagnostic markers, hepatic triglycerides, non-esterified fatty acids, and total bile acids were found in Fxr-null mice that had drunk water containing 0.5% taurine for four weeks. Hepatic but not serum taurine concentrations were significantly increased in these mice. The expression levels of oxidative stress-related genes (Hmox1 and Gsta1) and fatty acid synthetic genes (Acc1 and Scd1) were significantly decreased in these mice. These results suggest that drinking taurine improves hepatic steatosis and dysfunction caused by a lack of FXR.


Assuntos
Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/genética , Taurina/uso terapêutico , Acetil-CoA Carboxilase , Animais , Modelos Animais de Doenças , Feminino , Glutationa Transferase , Heme Oxigenase-1 , Isoenzimas , Proteínas de Membrana , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo/genética , Receptores Citoplasmáticos e Nucleares , Estearoil-CoA Dessaturase
9.
Am J Physiol Gastrointest Liver Physiol ; 318(3): G554-G573, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31984784

RESUMO

Bile acid synthesis is the most significant pathway for catabolism of cholesterol and for maintenance of whole body cholesterol homeostasis. Bile acids are physiological detergents that absorb, distribute, metabolize, and excrete nutrients, drugs, and xenobiotics. Bile acids also are signal molecules and metabolic integrators that activate nuclear farnesoid X receptor (FXR) and membrane Takeda G protein-coupled receptor 5 (TGR5; i.e., G protein-coupled bile acid receptor 1) to regulate glucose, lipid, and energy metabolism. The gut-to-liver axis plays a critical role in the transformation of primary bile acids to secondary bile acids, in the regulation of bile acid synthesis to maintain composition within the bile acid pool, and in the regulation of metabolic homeostasis to prevent hyperglycemia, dyslipidemia, obesity, and diabetes. High-fat and high-calorie diets, dysbiosis, alcohol, drugs, and disruption of sleep and circadian rhythms cause metabolic diseases, including alcoholic and nonalcoholic fatty liver diseases, obesity, diabetes, and cardiovascular disease. Bile acid-based drugs that target bile acid receptors are being developed for the treatment of metabolic diseases of the liver.


Assuntos
Ácidos e Sais Biliares/metabolismo , Fígado Gorduroso/metabolismo , Fígado/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Fígado Gorduroso/diagnóstico , Fígado Gorduroso/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Acoplados a Proteínas-G/agonistas , Transdução de Sinais
10.
Biochimie ; 168: 198-209, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31715215

RESUMO

Chronic consumption of unhealthy diet and sedentary lifestyle induces fatty liver and metabolic complications. Adipocytes get overloaded with lipid succeeding low-grade inflammation and disrupting adipokine release. This research aims to investigate the effect of sitagliptin on white adipose tissue inflammation, adipokine level, metabolic syndrome, and fatty liver through 5' adenosine monophosphate-activated protein kinase (AMPK) pathway. In sixteen weeks of the experimental protocol, Swiss albino mice were kept in a standard environment and were fed 60% high-fat diet and 20% fructose water (HFFW) where they developed metabolic syndrome features, adipose tissue inflammation, and altered adipokine profile. Sitagliptin was administered for the last eight weeks. They were allocated to following six groups, control diet with regular water (1), HFFW only (2), HFFW and metformin 100 mg/kg (3), HFFW and sitagliptin 10 mg/kg (4), HFFW and sitagliptin 20 mg/kg (5), and HFFW and sitagliptin 30 mg/kg (6). Fasting serum insulin (FSI), glucagon-like peptide-1 (GLP-1), adipokines (adiponectin and leptin), serum lipid profile, hepatic lipid content, and white adipose tissue inflammation were assessed. Protein expression of P-AMPK, P-Acetyl co-a carboxylase (ACC), and mRNA expression of fatty acid metabolism genes were also evaluated in the liver. Sitagliptin significantly and effectively reversed metabolic syndrome complexity. FSI and GLP-1 levels were improved. A significant reduction in hepatic lipid content and oxidative stress was also observed. Also, sitagliptin significantly ameliorated adipose tissue inflammation and adiponectin levels at 20 mg/kg and 30 mg/kg. P-AMPK and P-ACC expression increased significantly. Moreover, expression of fatty acid synthesis genes was down-regulated, and fatty acid oxidation genes were up-regulated. Sitagliptin significantly ameliorated obesity-induced adipose tissue inflammation, metabolic syndrome, and fatty liver via regulation of adiponectin and AMPK levels in obese mice. Also, increased GLP-1 levels would have induced insulin-independent effects on adipose tissue and liver.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adiponectina/metabolismo , Fígado Gorduroso/tratamento farmacológico , Inflamação/tratamento farmacológico , Síndrome Metabólica/tratamento farmacológico , Fosfato de Sitagliptina/farmacologia , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Inflamação/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos
11.
Int J Med Sci ; 16(12): 1593-1603, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31839747

RESUMO

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and its pathogenesis and mechanism are intricate. In the present study, we aimed to evaluate the role of PPAR δ in LPS associated NAFLD and to investigate the signal transduction pathways underlying PPAR δ treatment in vitro. Material and Methods: L02 cells were exposed to palmitic acid (PA) and/or LPS in the absence or presence of PPAR δ inhibition and/or activation. Results: LPS treatment markedly increased lipid deposition, FFA contents, IL-6 and TNF-α levels, and cell apoptosis in PA treatment (NAFLD model). PPAR δ inhibition protects L02 cells against LPS-induced lipidosis and injury. Conversely, the result of PPAR δ activation showed the reverse trend. LPS+PA treatment group significantly decreases the relative expression level of IRS-1, PI3K, AKT, phosphorylation of AKT, TLR-4, MyD88, phosphorylation of IKKα, NF-κB, Bcl-2 and increases the relative expression level of Bax, cleaved caspase 3 and cleaved caspase 8, compared with the cells treated with NAFLD model. PPAR δ inhibition upregulated the related proteins' expression level in insulin resistance and inflammation pathway and downregulated apoptotic relevant proteins. Instead, PPAR δ agonist showed the reverse trend. Conclusion: Our data show that PPAR δ inhibition reduces steatosis, inflammation and apoptosis in LPS-related NAFLD damage, in vitro. PPAR δ may be a potential therapeutic implication for NAFLD.


Assuntos
Fígado Gorduroso/tratamento farmacológico , Lipidoses/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , PPAR delta/genética , Substâncias Protetoras/farmacologia , Apoptose/efeitos dos fármacos , Células Cultivadas , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Hepatócitos/efeitos dos fármacos , Humanos , Lipidoses/genética , Lipidoses/metabolismo , Lipidoses/patologia , Lipídeos/genética , Lipopolissacarídeos/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , PPAR delta/agonistas , PPAR delta/antagonistas & inibidores , Ácido Palmítico/toxicidade , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tiazóis/farmacologia
12.
Lipids Health Dis ; 18(1): 234, 2019 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-31883528

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide, although its pathogenesis remains to be elucidated. A recent study revealed that hepatic Niemann-Pick C1-Like 1 (NPC1L1), a cholesterol re-absorber from bile to the liver expressed on the bile canalicular membrane, is an exacerbation factor of NAFLD. Indeed, transgenic mice with hepatic expression of human NPC1L1 under a liver-specific promoter (L1-Tg mice) developed steatosis with a high-fat diet (HFD) containing cholesterol within a few weeks. However, the mechanism underlying diet-induced hepatic NPC1L1-mediated lipid accumulation is poorly defined. METHODS: To achieve a deeper understanding of steatosis development in L1-Tg mice, the biochemical features of hepatic NPC1L1-mediated steatosis were investigated. Hemizygous L1-Tg mice and wild-type littermate controls fed a HFD or control-fat diet were used. At the indicated time points, the livers were evaluated for cholesterol and triglyceride (TG) contents as well as mRNA levels of hepatic genes involved in the maintenance of lipid homeostasis. The hepatic ability to secrete very low-density lipoprotein (VLDL)-TG was also investigated. RESULTS: Unlike the livers of wild-type mice that have little expression of hepatic Npc1l1, the livers of L1-Tg mice displayed time-dependent changes that indicated steatosis formation. In steatosis, there were three different stages of development: mild accumulation of hepatic cholesterol and TG (early stage), acceleration of hepatic TG accumulation (middle stage), and further accumulation of hepatic cholesterol (late stage). In the early stage, between WT and L1-Tg mice fed a HFD for 2 weeks, there were no significant differences in the hepatic expression of Pparα, Acox1, Fat/Cd36, Srebf1, and Srebf2; however, the hepatic ability to secrete VLDL-TG decreased in L1-Tg mice (P < 0.05). Furthermore, this decrease was completely prevented by administration of ezetimibe, an NPC1L1-selective inhibitor. CONCLUSION: Hepatic NPC1L1 exacerbates diet-induced steatosis, which was accompanied by decreased hepatic ability of VLDL-TG secretion. The obtained results provide a deeper understanding of L1-Tg mice as a promising NAFLD animal model that is able to re-absorb biliary-secreted cholesterol similar to humans. Furthermore, this work supports further studies of the pathophysiological impact of re-absorbed biliary cholesterol on the regulation of hepatic lipid homeostasis.


Assuntos
VLDL-Colesterol/genética , Fígado Gorduroso/genética , Reabsorção Intestinal/genética , Proteínas de Membrana Transportadoras/genética , Animais , Azetidinas/farmacologia , Bile/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ezetimiba/farmacologia , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/fisiopatologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/genética , Hipercolesterolemia/fisiopatologia , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Transgênicos , Triglicerídeos/genética
13.
Molecules ; 24(22)2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31703459

RESUMO

This study describes the chemical constituents of Albiziae Cortex and their ability to ameliorate steatosis and promote proliferation and anti-oxidation in vitro. Together, five known lignan glycosides, (7S,8R)-erythro-syringylglycerol-ß-O-4'-sinapyl ether 9-O-ß-D-glucopyranoside (1), (+)-lyoniresinol-9'-O-gluco-side (2), (-)-lyoniresinol-9'-O-glucoside (3), picraquassioside C (4), and icariside E5 (5), were isolated from the Albiziae Cortex. Their structures were elucidated by extensive NMR and high-resolution mass spectrometry analysis and compared with reported data. Oil Red O staining results revealed that compounds 1, 2, and 3 attenuated lipid accumulation and lipid metabolic disorders in FFAs (oleate/palmitate, 2:1 ratio, 0.3 mM)-exposed HepG2 cells. The Cell Counting Kit 8 (CCK-8) assay results revealed that compounds 1 and 5 can significantly promote human umbilical vein endothelial cell (HUVEC) proliferation; meanwhile, these compounds did not exhibit significant cytotoxicity against HUVECs. In addition, 2',7'-dichlorofluorescein diacetate (DCFH-DA) staining results revealed that high glucose (HG)-induced reactive oxygen species (ROS) production was abolished by compounds 1, 2, and 3. This is the first report of the isolation of lignan skeletons from the genus Albizzia julibrissin with the ability to ameliorate steatosis and promote proliferation and anti-oxidation activities.


Assuntos
Albizzia/química , Antioxidantes , Proliferação de Células/efeitos dos fármacos , Fígado Gorduroso/tratamento farmacológico , Lignanas/química , Antioxidantes/química , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana , Humanos , Espectrometria de Massas , Ressonância Magnética Nuclear Biomolecular , Ácido Oleico/metabolismo , Oxirredução , Ácido Palmítico/metabolismo
14.
Metabolism ; 101: 154001, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31672448

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western societies and a major cause of hepatic disease worldwide. Its more severe type, namely nonalcoholic steatohepatitis (NASH), may result in the development of cirrhosis and hepatocellular carcinoma. NAFLD, and especially NASH, are also associated with increased cardiovascular morbidity and mortality. Type 2 diabetes mellitus (T2DM) predisposes to NAFLD development and progression via insulin resistance and hyperglycemia. It has also been reported that the majority of T2DM patients have NAFLD/NASH, thus potentially further increasing their cardiometabolic risk. Current guidelines recommend to screen for NAFLD in all T2DM patients and vice-versa. Lifestyle remains the first-line therapeutic option for NAFLD/NASH. Among antidiabetic drugs, pioglitazone was shown to improve histological features of NASH. More recently, there is an increasing interest regarding the effects of newer anti-diabetic drugs, such as dipeptidyl peptidase 4 inhibitors (DPP-4i), sodium glucose cotransporter 2 inhibitors (SGLT2i), and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on NAFLD/NASH. The present narrative review considers the up-to-date data on the impact of DPP-4i, SGLT2i, and GLP-1 RAs on biochemical and/or histological markers of NAFLD/NASH. The potential clinical implications of these findings in daily practice are also discussed. Taking into consideration the global increasing prevalence of NAFLD/NASH, therapeutic options that can prevent or treat this disease will exert considerable benefits on human health.


Assuntos
Fígado Gorduroso/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/complicações , Pioglitazona/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
15.
J Med Food ; 22(12): 1189-1198, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31634046

RESUMO

Metabolic syndrome is recognized as a proinflammatory condition leading to hepatic steatosis and nonalcoholic steatohepatitis (NASH). We tested the effects of a succulent species Hoodia parviflora N.E. Br., of the genus Hoodia sweetex Dence, on animal models of NASH and insulin resistance (ob/ob mouse and the sand rat Psammomys obesus). IL6 secretion was evaluated by ELISA and hepatic signal transducer and activator of transcription 3 by Western blot. We followed liver enzymes, weight, glucose, hepatic histology, hepatic triglycerides (TGs), and total fat and serum insulin. Oral administration of extracts derived from H. parviflora alleviated the insulin resistance manifested by improved glucose tolerance tests. Treatment alleviated the liver injury noted by a decrease in liver enzyme levels, improved intrahepatic TG content, total hepatic fat, and improved hepatic histology. Similarly, treatment with H. parviflora reduced hepatic inflammation in mice with Concanavalin A-induced hepatitis. These effects were independent of food consumption and weight. H. parviflora was associated with alleviated insulin resistance, hepatic steatosis, and liver injury. The data support its use as a liver protector.


Assuntos
Hoodia/química , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Extratos Vegetais/farmacologia , Administração Oral , Animais , Glicemia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Diabetes Mellitus Tipo 2 , Modelos Animais de Doenças , Fígado Gorduroso/tratamento farmacológico , Teste de Tolerância a Glucose , Hepatite , Insulina/sangue , Interleucina-6/metabolismo , Fígado/lesões , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Triglicerídeos/sangue
16.
J Physiol Pharmacol ; 70(4)2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31642820

RESUMO

There is an established correlation between the PNPLA3 rs738409 C > G single nucleotide polymorphism (SNP) and hepatic steatosis and fibrosis in hepatitis C virus (HCV) infected patients. However not all data is convergent regarding the exact impact of this SNP on the pattern of disease progression in different clinical settings. In this study, we aimed to further bridge the knowledge gap on this topic by investigating the role of the G allele in promoting steatosis, fibrosis and disease progression in relation to other metabolic and anthropometric host factors. Two hundred and fifty consecutive patients, previously diagnosed with chronic hepatitis C (CHC) underwent liver biopsy. Histology was assessed using the Metavir scoring system. Transient elastography was used for follow-up. Ninety-eight patients were genotyped for PNPLA3 rs738409 and followed up for fibrosis progression. PNPLA3 rs738409[G] allele was significantly correlated with severe steatosis (P = 0.04), severe fibrosis at the time of enrollment (P = 0.0005) and fibrosis progression with an OR of 10.31 (95% CI 1.06 - 99.59, P = 0.04), after a mean follow-up time of 62.85 (95%CI: 52.21 - 76.15) months. Severe steatosis at the time of enrollment had an OR of 11.02 (95% CI 1.48 - 82.09, P = 0.01) for the association with fibrosis progression. The HOMA-IR index was also positively correlated with severe fibrosis (P = 0.03) and fibrosis progression on univariate analysis (P = 0.02). PNPLA3 rs738409[G] allele is a reliable predictor for steatosis and fibrosis in CHC. The presence of G allele, along with severe steatosis and insulin resistance are significant predictors for fibrosis progression.


Assuntos
Fígado Gorduroso/genética , Hepatite C Crônica/genética , Lipase/genética , Cirrose Hepática/genética , Proteínas de Membrana/genética , Antivirais/uso terapêutico , Progressão da Doença , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/patologia , Fígado Gorduroso/virologia , Feminino , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Humanos , Interferon alfa-2/uso terapêutico , Interferon-alfa/uso terapêutico , Fígado/patologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/uso terapêutico , Polimorfismo de Nucleotídeo Único , RNA Viral/sangue , Proteínas Recombinantes/uso terapêutico , Ribavirina/uso terapêutico
17.
Nutrients ; 11(10)2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31623374

RESUMO

Inflammation and oxidative stress play a key role in the pathophysiology of advanced chronic liver disease (ACLD) and portal hypertension (PH). Considering the current lack of effective treatments, we evaluated an anti-inflammatory and antioxidant nutraceutical rich in docosahexaenoic acid (DHA) as a possible therapy for ACLD. We investigated the effects of two-week DHA supplementation (500 mg/kg) on hepatic fatty acids, PH, oxidative stress, inflammation, and hepatic stellate cell (HSC) phenotype in rats with ACLD. Additionally, the effects of DHA were evaluated in murine macrophages and human HSC. In contrast to vehicle-treated animals, cirrhotic rats receiving DHA reestablished a healthy hepatic fatty acid profile, which was associated with an improvement in PH. The mechanisms underlying this hemodynamic improvement included a reduction in oxidative stress and inflammation, as well as a marked HSC deactivation, confirmed in human HSC. Experiments with cultured macrophages showed that treatment with DHA protects against pro-inflammatory insults. The present preclinical study demonstrates that a nutraceutical rich in DHA significantly improves PH in chronic liver disease mainly by suppressing inflammation and oxidative stress-driven HSC activation, encouraging its evaluation as a new treatment for PH and cirrhosis.


Assuntos
Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem , Suplementos Nutricionais/análise , Ácidos Docosa-Hexaenoicos/administração & dosagem , Hipertensão Portal/tratamento farmacológico , Animais , Doença Crônica , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/análise , Ácidos Graxos/análise , Ácidos Graxos Ômega-3/análise , Fígado Gorduroso/tratamento farmacológico , Células Estreladas do Fígado/efeitos dos fármacos , Humanos , Fígado/química , Hepatopatias/fisiopatologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley
18.
J Agric Food Chem ; 67(44): 12208-12218, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31608624

RESUMO

To explore the role of apple polyphenol extract (APE) in ameliorating hepatic steatosis and the potential mechanisms involved, we conducted this study. Thirty-three male C57BL/6 mice were randomly divided into three groups: high-fat diet (HFD) with aseptic water ig. (CON), HFD with 125 or 500 mg/(kg·bw·day) APE ig., namely 100 or 400 mg/(kg·bw·day) apple polyphenols (LAP or HAP) for 12 weeks. Compared with the CON group, the APE treatment significantly decreased the body weight gain and increased the ratio of serum albumin/globulin. High dose of APE treatment significantly decreased the liver weight, reduced the hepatic contents of triglyceride and cholesterol, and improved the histopathological features of hepatic steatosis, accompanied by significantly upregulated protein expressions of LKB1, phosphorylated-AMPK, phosphorylated-ACC, and SIRT1, downregulated mTOR, p70 s6k, and HMGCR in the liver, increased mRNA expressions of Ampk and Cyp27a1, and reduced expressions of Srebp-1c, Fas, and Hmgcr. Our data provided new evidence supporting the preventive role of 500 mg/(kg·bw·day) APE treatment in the HFD-induced hepatic steatosis in C57BL/6 mice via the LKB1/AMPK pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Ácido Clorogênico/administração & dosagem , Fígado Gorduroso/tratamento farmacológico , Flavonoides/administração & dosagem , Proteínas Serina-Treonina Quinases/metabolismo , Taninos/administração & dosagem , Proteínas Quinases Ativadas por AMP/genética , Animais , Colesterol , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/etiologia , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Humanos , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Serina-Treonina Quinases/genética , Triglicerídeos/metabolismo
19.
Int J Mol Sci ; 20(18)2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31491949

RESUMO

Obesity characterized by adiposity and ectopic fat accumulation is associated with the development of non-alcoholic fatty liver disease (NAFLD). Treatments that stimulate lipid utilization may prevent the development of obesity and comorbidities. This study evaluated the potential anti-obesogenic hepatoprotective effects of combined treatment with L-carnitine and nicotinamide riboside, i.e., components that can enhance fatty acid transfer across the inner mitochondrial membrane and increase nicotinamide adenine nucleotide (NAD+) levels, which are necessary for ß-oxidation and the TCA cycle, respectively. Ldlr -/-.Leiden mice were treated with high-fat diet (HFD) supplemented with L-carnitine (LC; 0.4% w/w), nicotinamide riboside (NR; 0.3% w/w) or both (COMBI) for 21 weeks. L-carnitine plasma levels were reduced by HFD and normalized by LC. NR supplementation raised its plasma metabolite levels demonstrating effective delivery. Although food intake and ambulatory activity were comparable in all groups, COMBI treatment significantly attenuated HFD-induced body weight gain, fat mass gain (-17%) and hepatic steatosis (-22%). Also, NR and COMBI reduced hepatic 4-hydroxynonenal adducts. Upstream-regulator gene analysis demonstrated that COMBI reversed detrimental effects of HFD on liver metabolism pathways and associated regulators, e.g., ACOX, SCAP, SREBF, PPARGC1B, and INSR. Combination treatment with LC and NR exerts protective effects on metabolic pathways and constitutes a new approach to attenuate HFD-induced obesity and NAFLD.


Assuntos
Carnitina/farmacologia , Fígado Gorduroso/metabolismo , Niacinamida/análogos & derivados , Obesidade/metabolismo , Animais , Biomarcadores , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/genética , Regulação da Expressão Gênica , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Niacinamida/farmacologia , Obesidade/tratamento farmacológico , Obesidade/genética , Estresse Oxidativo , Transdução de Sinais
20.
Am J Chin Med ; 47(6): 1253-1270, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31488034

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disorder associated with features of metabolic syndrome and oxidative stress. We examined the mechanism by which the combined extracts of Rhus verniciflua and Eucommia ulmoides extracts (ILF-RE) regulate hepatic dyslipidemia in an established NAFLD model, high-fat diet (HFD)-induced lipid dysmetabolism in rats. ILF-RE attenuated alanine aminotransferase (ALT) by 1.5% (p<0.05), aspartate aminotransferase (AST) by 1.5% (p<0.05), triglycerides by 1.5% (p<0.05), cholesterol by 2.0% (p<0.05), and lipid peroxidation by 1.5% (p<0.05) in the NAFLD model. ILF-RE, recently shown to have anti-oxidant properties, also inhibited hepatic ROS accumulation by 1.68% (p<0.05) and regulated ER-redox imbalance, a key phenomenon of ER stress. Due to nutrient overload stress-associated protein folding, ER stress and downstream SREBP-lipogenic transcription signaling were highly activated, and the mTORC1-AMPK axis was also disturbed, leading to hepatic steatosis. ILF-RE results in recovery from hepatic conditions induced by nutrient-based protein folding stress signaling and the ER stress-SREBP and AMPK-mTORC1-SREBP1 axes. Based on these results, ILF-RE is suggested to be a potential therapeutic strategy for hepatic steatosis and may represent a promising novel agent for the prevention and treatment of NAFLD.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Eucommiaceae/química , Fígado Gorduroso/etiologia , Fígado Gorduroso/prevenção & controle , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Antioxidantes , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Glucosídeos Iridoides/isolamento & purificação , Glucosídeos Iridoides/farmacologia , Glucosídeos Iridoides/uso terapêutico , Iridoides/isolamento & purificação , Iridoides/farmacologia , Iridoides/uso terapêutico , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
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