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1.
Metabolism ; 109: 154283, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32497536

RESUMO

BACKGROUND: Absolute dietary fat intake but even more so fatty acid pattern is discussed to be critical in the development of non-alcoholic fatty liver disease (NAFLD). Here, we determined if switching a butterfat enriched diet to a rapeseed oil (RO) enriched diet affects progression of an existing NAFLD and glucose intolerance in mice. METHODS: For eight weeks, female C57Bl/6J mice were either fed a liquid control (C) or a butterfat-, fructose- and cholesterol-rich diet (BFC, 25E% butterfat) to induce early signs of steatohepatitis and glucose intolerance in mice. For additional five weeks mice received either BFC or C or a fat-, fructose- and cholesterol-rich and control diet, in which butterfat was replaced with RO (ROFC and CRO). Markers of glucose metabolism, liver damage and intestinal barrier were assessed. RESULTS: Exchanging butterfat with RO attenuated the progression of BFC diet-induced NAFLD and glucose intolerance. Beneficial effects of RO were associated with lower portal endotoxin levels and an attenuation of the induction of the toll-like receptor-4-dependent signaling cascades in liver. Peroxisome proliferator-activated receptor γ activity was induced in small intestine of ROFC-fed mice. CONCLUSION: Taken together, exchanging butterfat with RO attenuated the progression of diet-induced steatohepatitis and glucose intolerance in mice.


Assuntos
Manteiga/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Intolerância à Glucose/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Óleo de Brassica napus/uso terapêutico , Animais , Progressão da Doença , Endotoxinas/metabolismo , Feminino , Rim/química , Camundongos , Camundongos Endogâmicos C57BL , Receptor 4 Toll-Like
2.
Life Sci ; 256: 117990, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32574665

RESUMO

AIM: Luteolin and lycopene are common natural products, widely existing in nature, and both of which were reported to have various biological functions including anti-inflammatory, anti-obesity and anti-NAFLD. In the present study, we aimed to evaluate the therapeutic efficacy of luteolin and lycopene in combination and its latent molecular mechanisms in vitro and in vivo models of NAFLD. MAIN METHODS: Sodium palmitate (PA)-induced steatotic HepG2 cells and primary hepatocytes, and high-fat diet-induced C57BL/6J obese mice were treated with luteolin, lycopene and their combination. Metabolic parameters were measured. KEY FINDINGS: We found that luteolin (20 µM) + lycopene (10 µM) was the best therapeutic combination in PA-induced HepG2 cells, and significantly improve cell viability and lipid accumulation in PA-induced HepG2 cells and primary hepatocytes. In addition, luteolin (20 mg/kg) + lycopene (20 mg/kg) could ameliorate increased body weight and hepatocyte steatosis; regulate serum triglycerides, serum total cholesterol, hepatic triglycerides and hepatic total cholesterol; decrease serum alanine transaminase and aspartate transaminase. Furthermore, in vivo and in vitro, luteolin, lycopene and their combination had no effect on Sirt1 expression, but all of them could upregulate the expression of NAMPT, which could increase the level of NAD+, the co-substrate of Sirt1, indirectly activating Sirt1/AMPK pathway, and then inhibited lipogenesis and increased ß-oxidation, defensing the "first hit"; they also inactivated nuclear factor-κB (NF-κB) and decreased the levels of IL-6, IL-1ß and TNF-α, defensing the "second hit". SIGNIFICANCE: Thus, luteolin and lycopene in combination can effectively ameliorate "two-hit" in NAFLD through activation of the Sirt1/AMPK pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Luteolina/administração & dosagem , Licopeno/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Sirtuína 1/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Células Hep G2 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Substâncias Protetoras/administração & dosagem , Distribuição Aleatória
3.
Am J Physiol Gastrointest Liver Physiol ; 318(6): G989-G999, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32363890

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is associated with testosterone deficiency. However, NAFLD patients generally do not respond to treatment with testosterone alone. We investigated the innate immune mechanisms underlying the effects of treatment with testosterone alone, estrogen alone, or combined testosterone and estrogen on high-fat diet (HFD)-induced NAFLD due to testosterone deficiency. Orchiectomized (OCX) male Rag2-/- mice were used as a model of testosterone deficiency. To assess NAFLD severity, NAFLD activity score (NAS) is adopted. Moreover, immunological change was analyzed by multicolor flow cytometry. Treatment with both testosterone and estrogen significantly decreased body weight to that of the sham mice/normal diet (ND). NAS and liver fibrosis in OCX-HFD mice were significantly deteriorated, and treatment with testosterone and estrogen improved same as sham-ND mice. HFD increased the ratio of both type 2 and 3 innate lymphoid cells (ILC2s and ILC3s) to CD45-positive cells in the liver. Treatment with testosterone alone decreased the ratio of ILC2 to CD45 but not the ILC3-to-CD45 ratio. Addition of estrogen to the treatment reduced the ratios of ILC2-to-CD45 and ILC3-to-CD45 to the same level observed in sham-HFD mice. Moreover, OCX-HFD mice had a decreased proportion of M2 macrophages compared with sham-ND mice. Treatment with testosterone alone did not restore the proportion of M2 macrophages; however, combination treatment with both estrogen and testosterone increased that to the same level as that in sham-HFD mice. Treatment with both testosterone and estrogen improves liver fibrosis and decreases ILC3 and increases M2 macrophage abundance in the liver.NEW & NOTEWORTHY The progression of nonalcoholic fatty liver disease (NAFLD) is associated with testosterone deficiency. NAFLD patients generally do not respond to treatment with testosterone alone. In animal studies, treatment with testosterone and estrogen reduced the ratios of ILC2:CD45 and ILC3:CD45 and increased M2 macrophages in liver. Our study suggests, based on our immunological data, that a combination of estrogen and testosterone may be clinically relevant for the treatment of NAFLD in patients with male menopause.


Assuntos
Estradiol/farmacologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Testosterona/farmacologia , Aminoácidos , Animais , Carcinoma Hepatocelular , Linhagem Celular Tumoral , Cromo , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Dieta Hiperlipídica/efeitos adversos , Regulação para Baixo , Estradiol/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Insulina , Cirrose Hepática , Neoplasias Hepáticas , Masculino , Camundongos , Camundongos Knockout , Ácidos Nicotínicos , Hepatopatia Gordurosa não Alcoólica/patologia , Orquiectomia , Células RAW 264.7 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores CCR2/genética , Receptores CCR2/metabolismo , Testosterona/administração & dosagem , Testosterona/deficiência , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
4.
Am J Physiol Endocrinol Metab ; 318(4): E492-E503, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32017594

RESUMO

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have been reported to improve obesity, diabetes, and nonalcoholic fatty liver disease (NAFLD) in addition to exercise training, whereas the combined effects remain to be elucidated fully. We investigated the effect of the combination of the SGLT2i canagliflozin (CAN) and exercise training in high-fat diet-induced obese mice. High-fat diet-fed mice were housed in normal cages (sedentary; Sed) or wheel cages (WCR) with or without CAN (0.03% of diet) for 4 wk. The effects on obesity, glucose metabolism, and hepatic steatosis were evaluated in four groups (Control/Sed, Control/WCR, CAN/Sed, and CAN/WCR). Numerically additive improvements were found in body weight, body fat mass, blood glucose, glucose intolerance, insulin resistance, and the fatty liver of the CAN/WCR group, whereas CAN increased food intake and reduced running distance. Exercise training alone, CAN alone, or both did not change the weight of skeletal muscle, but microarray analysis showed that each resulted in a characteristic change of gene expression in gastrocnemius muscle. In particular, in the CAN/WCR group, there was acceleration of the angiogenesis pathway and suppression of the adipogenesis pathway compared with the CAN/Sed group. In conclusion, the combination of an SGLT2i and exercise training improves obesity, insulin resistance, and NAFLD in an additive manner. Changes of gene expression in skeletal muscle may contribute, at least in part, to the improvement of obesity and insulin sensitivity.


Assuntos
Canagliflozina/farmacologia , Dieta Hiperlipídica , Condicionamento Físico Animal/fisiologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/crescimento & desenvolvimento , Animais , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Intolerância à Glucose , Teste de Tolerância a Glucose , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiologia , Neovascularização Fisiológica/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Obesidade/metabolismo , Obesidade/prevenção & controle
5.
Nutr Metab Cardiovasc Dis ; 30(4): 709-716, 2020 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-32007335

RESUMO

BACKGROUND AND AIMS: Mediterranean diet has been associated with decreased cardiovascular morbidity and mortality. Both fish and olive oil are key components of this diet. Therefore, we compared their effects on nonalcoholic fatty liver disease (NAFLD) and atherogenesis in a mouse model, fed a high fat diet. METHODS AND RESULTS: Forty nine, female LDL receptor knockout (LDLR KO) mice were allocated into 3 groups and fed an atherogenic high fat (HF) diet for 9 weeks. The HF group was fed a high fat diet alone. A HF + OO group was fed a HF diet with added olive oil (60 ml/kg feed), and the third group (HF + FO) was fed a HF diet with added fish oil (60 ml/kg feed). Both additions of fish and olive oil, significantly decreased plasma cholesterol elevation compared to HF diet. Nevertheless, only fish oil addition reduced significantly atherosclerotic lesion area by 51% compared to HF group. Liver levels of eicosapentenoic (EPA) and docosahexaenoic (DHA) acids were several folds higher in HF + FO group than in HF and HF + OO groups. Liver levels of oleic acid were higher in HF + OO compared to the other groups. Moreover, Fish oil addition significantly decreased NAFLD scores related to steatosis and inflammation and lowered the expression of the inflammatory genes interleukin 6 (IL6) and monocyte chemoattractant protein 1 (MCP1). CONCLUSION: These results suggest that fish oil addition on top of an atherogenic, HF diet, is beneficial, while olive oil is not, in its effect on plaque formation and NAFLD in LDLR KO mice.


Assuntos
Aterosclerose/prevenção & controle , Dieta Hiperlipídica , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácido Eicosapentaenoico/administração & dosagem , Azeite de Oliva/administração & dosagem , Animais , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/patologia , Biomarcadores/sangue , Quimiocina CCL2/metabolismo , Colesterol/sangue , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/metabolismo , Ácido Eicosapentaenoico/metabolismo , Feminino , Interleucina-6/metabolismo , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Ácido Oleico/administração & dosagem , Ácido Oleico/metabolismo , Placa Aterosclerótica , Receptores de LDL/deficiência , Receptores de LDL/genética , Fatores de Tempo
6.
Am J Physiol Gastrointest Liver Physiol ; 318(3): G582-G609, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32003601

RESUMO

To investigate the role of bile acids (BAs) in the pathogenesis of diet-induced nonalcoholic steatohepatitis (NASH), we fed a "Western-style diet" [high fructose, high fat (HFF)] enriched with fructose, cholesterol, and saturated fat for 10 wk to juvenile Iberian pigs. We also supplemented probiotics with in vitro BA deconjugating activity to evaluate their potential therapeutic effect in NASH. Liver lipid and function, cytokines, and hormones were analyzed using commercially available kits. Metabolites, BAs, and fatty acids were measured by liquid chromatography-mass spectrometry. Histology and gene and protein expression analyses were performed using standard protocols. HFF-fed pigs developed NASH, cholestasis, and impaired enterohepatic Farnesoid-X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling in the absence of obesity and insulin resistance. Choline depletion in HFF livers was associated with decreased lipoprotein and cholesterol in serum and an increase of choline-containing phospholipids in colon contents and trimethylamine-N-oxide in the liver. Additionally, gut dysbiosis and hyperplasia increased with the severity of NASH, and were correlated with increased colonic levels of choline metabolites and secondary BAs. Supplementation of probiotics in the HFF diet enhanced NASH, inhibited hepatic autophagy, increased excretion of taurine and choline, and decreased gut microbial diversity. In conclusion, dysregulation of BA homeostasis was associated with injury and choline depletion in the liver, as well as increased biliary secretion, gut metabolism and excretion of choline-based phospholipids. Choline depletion limited lipoprotein synthesis, resulting in hepatic steatosis, whereas secondary BAs and choline-containing phospholipids in colon may have promoted dysbiosis, hyperplasia, and trimethylamine synthesis, causing further damage to the liver.NEW & NOTEWORTHY Impaired Farnesoid-X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling and cholestasis has been described in nonalcoholic fatty liver disease (NAFLD) patients. However, therapeutic interventions with FXR agonists have produced contradictory results. In a swine model of pediatric nonalcoholic steatohepatitis (NASH), we show that the uncoupling of intestinal FXR-FGF19 signaling and a decrease in FGF19 levels are associated with a choline-deficient phenotype of NASH and increased choline excretion in the gut, with the subsequent dysbiosis, colonic hyperplasia, and accumulation of trimethylamine-N-oxide in the liver.


Assuntos
Ácidos e Sais Biliares/metabolismo , Colina/metabolismo , Colo/metabolismo , Colo/microbiologia , Fatores de Crescimento de Fibroblastos/metabolismo , Microbioma Gastrointestinal , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Fatores Etários , Animais , Colo/patologia , Modelos Animais de Doenças , Disbiose , Feminino , Hiperplasia , Fígado/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/microbiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Probióticos/administração & dosagem , Transdução de Sinais , Sus scrofa
7.
Am J Physiol Gastrointest Liver Physiol ; 318(3): G428-G438, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31928222

RESUMO

Enhanced free fatty acid (FFA) flux from adipose tissue (AT) to liver plays an important role in the development of nonalcoholic steatohepatitis (NASH) and alcohol-associated liver disease (AALD). We determined the effectiveness of nanoformulated superoxide dismutase 1 (Nano) in attenuating liver injury in a mouse model exhibiting a combination of NASH and AALD. Male C57BL6/J mice were fed a chow diet (CD) or a high-fat diet (HF) for 10 wk followed by pair feeding of the Lieber-DeCarli control (control) or ethanol (ET) diet for 4 wk. Nano was administered once every other day for the last 2 wk of ET feeding. Mice were divided into 1) CD + control diet (CD + Cont), 2) high-fat diet (HF) + control diet (HF + Cont), 3) HF + Cont + Nano, 4) HF + ET diet (HF + ET), and 5) HF + ET + Nano. The total fat mass, visceral AT mass (VAT), and VAT perilipin 1 content were significantly lower only in HF + ET-fed mice but not in HF + ET + Nano-treated mice compared with controls. The HF + ET-fed mice showed an upregulation of VAT CYP2E1 protein, and Nano abrogated this effect. We noted a significant rise in plasma FFAs, ALT, and monocyte chemoattractant protein-1 in HF + ET-fed mice, which was blunted in HF + ET + Nano-treated mice. HF + ET-induced increases in hepatic steatosis and inflammatory markers were attenuated upon Nano treatment. Nano reduced hepatic CYP2E1 and enhanced catalase levels in HF + ET-fed mice with a concomitant increase in SOD1 protein and activity in liver. Nano was effective in attenuating AT and liver injury in mice exhibiting a combination of NASH and AALD, partly via reduced CYP2E1-mediated ET metabolism in these organs.NEW & NOTEWORTHY Increased free fatty acid flux from adipose tissue (AT) to liver accompanied by oxidative stress promotes nonalcoholic steatohepatitis (NASH) and alcohol-associated liver injury (AALD). Obesity increases the severity of AALD. Using a two-hit model involving a high-fat diet and chronic ethanol feeding to mice, and treating them with nanoformulated superoxide dismutase (nanoSOD), we have shown that nanoSOD improves AT lipid storage, reduces CYP2E1 in AT and liver, and attenuates the combined NASH/AALD in mice.


Assuntos
Citocromo P-450 CYP2E1/metabolismo , Fígado Gorduroso Alcoólico/prevenção & controle , Gordura Intra-Abdominal/efeitos dos fármacos , Fígado/efeitos dos fármacos , Nanopartículas , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Superóxido Dismutase-1/administração & dosagem , Adiposidade/efeitos dos fármacos , Animais , Catalase/metabolismo , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Modelos Animais de Doenças , Composição de Medicamentos , Fígado Gorduroso Alcoólico/enzimologia , Fígado Gorduroso Alcoólico/genética , Fígado Gorduroso Alcoólico/patologia , Regulação da Expressão Gênica , Gordura Intra-Abdominal/enzimologia , Gordura Intra-Abdominal/patologia , Lipólise/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Nanomedicina , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/efeitos dos fármacos , Perilipina-1/genética , Perilipina-1/metabolismo , Transdução de Sinais , Superóxido Dismutase-1/química
8.
Phytomedicine ; 67: 153140, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31884405

RESUMO

BACKGROUND: Hedansanqi Tiaozhi Tang extract (HTT) consists of Notoginseng, Danshen, Hawthorn and Lotus leaf from traditional Chinese medicine, which has significant therapeutic effects on hyperlipidemia in patients with non-alcoholic fatty liver disease (NAFLD). PURPOSE: This study sought to evaluate the pharmacological effects and molecular mechanism of HTT for the treatment of hyperlipidemia in adipocytes and animal model with NAFLD. METHODS: Quantitative phytochemical analysis of HTT was performed by HPLC. Antioxidant activity and the adipogenesis in 3T3-L1 cells were assessed. In the rat model induced by high-fat diet, lipid-related and antioxidant markers in serum and liver were detected. Moreover, the organ weights, non-alcoholic steatohepatitis (NASH) score and the levels of Nrf2 and HO-1 in liver sections were analyzed by tissue pathological techniques. RESULTS: 8 constituents were identified in HTT including saponins, flavonoids, alkaloids and others. HTT treatment enhanced antioxidant activities and promoted lipolysis in 3T3-L1 adipocytes. We also found that HTT inhibited weight gain, reduced the lipid profiles and improved the liver function and pathological characteristics induced by high-fat diet. In addition, HTT activated the Nrf2/HO-1 antioxidant pathway in the liver. CONCLUSION: HTT has protective effect against NAFLD in vitro and in vivo by activating the Nrf2/HO-1 antioxidant pathway.


Assuntos
Antioxidantes/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Heme Oxigenase (Desciclizante)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Células 3T3-L1 , Animais , Crataegus/química , Dieta Hiperlipídica/efeitos adversos , Medicamentos de Ervas Chinesas/química , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Compostos Fitoquímicos/análise , Ratos Sprague-Dawley
9.
J Nutr ; 150(4): 672-684, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31858105

RESUMO

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. Hepatic de novo lipogenesis (DNL) has been suggested to contribute to the pathogenesis of NAFLD. Recent studies have demonstrated that niacin (NA) modulates hepatic DNL through GPR109A. However, the underlying mechanism remains largely unknown. OBJECTIVES: This study aims to elucidate the potential molecular mechanism by which GPR109A inhibits hepatic DNL. METHODS: C57BL/6 wild-type (WT) and Gpr109a knockout (KO) mice (male, 5 wk old) were fed a high-fat diet (60% energy from fat) firstly for 6 wk to generate a diet-induced obese model. Subsequently, they were randomly divided into 4 groups for the next 8-9 wk: WT mice with oral water [WT + vehile (VE)], WT mice with oral NA (50 mM, dissolved in water) (WT + NA), KO mice with oral water (KO + VE), and KO mice with oral NA (50 mM) (KO + NA). Mechanisms were examined in HepG2 cells. Body composition, liver histology, biomarkers of hepatic function, lipid accumulation, and lipid synthesis signals in HepG2 cells were measured. RESULTS: Upon activation, GPR109A apparently protected against obesity and hepatic steatosis (P < 0.05). The concentrations of hepatic Tnf-α in the WT + NA group were about 50% of those in the WT + VE group (P < 0.05). The activities of serum alanine transaminase and aspartate transaminase were 26.7% and 53.5% lower in the WT + NA group than in the WT + VE group, respectively (P < 0.05). In HepG2 cells, activation of GPR109A resulted in remarkable inhibition of oleic acid-induced lipid accumulation via a protein kinase C-extracellular signal-regulated kinase-1/2-AMP-activated protein kinase signaling pathway. CONCLUSIONS: NA inhibits hepatic lipogenesis in C57BL/6 mice through a GPR109A-mediated signaling pathway, consistent with the mechanistic studies in HepG2 cells, suggesting its potential for treatment of NAFLD and other fatty liver diseases.


Assuntos
Adenilato Quinase/metabolismo , Lipogênese/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Niacina/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Receptores Acoplados a Proteínas-G/fisiologia , Animais , Dieta Hiperlipídica , Técnicas de Silenciamento de Genes , Células Hep G2 , Humanos , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/etiologia , Obesidade/prevenção & controle , Receptores Acoplados a Proteínas-G/deficiência , Transdução de Sinais
10.
Exp Mol Pathol ; 113: 104363, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31881201

RESUMO

Non-alcoholic steatohepatitis (NASH) is characterized by immune cell infiltration. Loss of the scaffold protein alpha-syntrophin (SNTA) protected mice from hepatic inflammation in the methionine-choline-deficient (MCD) diet model. Here, we determined increased numbers of macrophages and CD8+ T-cells in MCD diet induced NASH liver of wild type mice. In the mutant animals these NASH associated changes in immune cell composition were less pronounced. Further, there were more γδ T-cells in the NASH liver of the null mice. Galectin-3 protein in the hepatic non-parenchymal cell fraction was strongly induced in MCD diet fed wild type but not mutant mice. Antioxidant enzymes declined in NASH liver with no differences between the genotypes. To identify the target cells responsive to SNTA loss in-vitro experiments were performed. In the human hepatic stellate cell line LX-2, SNTA did not regulate pro-fibrotic or antioxidant proteins like alpha-smooth muscle actin or catalase. Soluble galectin-3 was, however, reduced upon SNTA knock-down and increased upon SNTA overexpression. SNTA deficiency neither affected cell proliferation nor cell death of LX-2 cells. In the macrophage cell line RAW264.7 low SNTA indeed caused higher galectin-3 production whereas release of TNF and cell viability were normal. Moreover, SNTA had no effect on hepatocyte chemerin and CCL2 expression. Overall, SNTA loss improved NASH without causing major effects in macrophage, hepatocyte and hepatic stellate cell lines. SNTA null mice fed the MCD diet had less body weight loss and this seems to contribute to improved liver health of the mutant mice.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Proteínas de Ligação ao Cálcio/deficiência , Galectina 3/metabolismo , Fígado/patologia , Macrófagos/patologia , Proteínas de Membrana/deficiência , Proteínas Musculares/deficiência , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Actinas/metabolismo , Animais , Antioxidantes/metabolismo , Peso Corporal , Proteínas de Ligação ao Cálcio/metabolismo , Catalase/metabolismo , Linhagem Celular , Proliferação de Células , Sobrevivência Celular , Quimiocina CCL2/metabolismo , Quimiocinas/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Ácido Graxo Sintases/metabolismo , Comportamento Alimentar , Heme Oxigenase-1/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Interleucina-6/metabolismo , L-Lactato Desidrogenase/metabolismo , Macrófagos/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Proteínas Musculares/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
11.
Nutrients ; 11(12)2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31847157

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is a comorbidity of obesity, which gradually develops from hepatic steatosis into steatohepatitis (NASH) and eventually even into fibrosis or hepatic carcinoma. To date, there has been no specific and effective treatment for NAFLD. Sarcopoterium spinosum extract (SSE) was found to improve insulin sensitivity. Recognizing the intimate link between insulin resistance and NAFLD, the aim of this study was to investigate the effectivity of SSE in the prevention and management of NAFLD at various severities. SSE was given to high-fat diet (HFD)-fed mice (steatosis model) or to mice given a Western diet (WD) in the short or long term (NASH prevention or treatment, respectively). SSE reduced body weight accumulation, improved glucose tolerance and insulin sensitivity and prevented the development of hepatic steatosis. SSE also blocked the progression of liver disease toward NASH in a dose-dependent manner. The expression of genes involved in lipid metabolism, inflammation, and antioxidant machinery was regulated by SSE in both models of steatosis and NASH development. However, SSE failed to reverse the hepatic damage in the advanced model of NASH. In summary, SSE might be considered as a botanical supplement for the prevention and treatment of hepatic steatosis, and for slowing the deterioration toward NASH.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Extratos Vegetais/farmacologia , Rosaceae , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Modelos Animais de Doenças , Progressão da Doença , Resistência à Insulina/fisiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Extratos Vegetais/administração & dosagem
12.
Nutrients ; 12(1)2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31861497

RESUMO

Consumption of omega-3 (n-3) polyunsaturated fatty acids (PUFA) is related to improvement in the inflammatory response associated with decreases in metabolic disorders of obesity, such as low-grade inflammation and hepatic steatosis. Linseed (Linum usitatissimum) oil is a primary source of n-3 fatty acids (FAs) of plant origin, particularly α-linolenic acid, and provides an alternative for the ingestion of n-3 PUFA by persons allergic to, or wishing to avoid, animal sources. In our study, we evaluated the effect of the consumption of different lipidic sources on metabolic and inflammatory parameters in Wistar rats. We split 56 male rats into four groups that were fed for 60 days with the following diets: sesame oil, (SO, Sesamum indicum), linseed oil (LO), SO + LO (SLO), and a control group (CG) fed with animal fat. Our results reveal that the use of LO or SLO produced improvements in the hepatic tissue, such as lower values of aspartate aminotransferase, liver weight, and hepatic steatosis. LO and SLO reduced the weight of visceral fats, weight gain, and mediated the inflammation through a decrease in interleukin (IL)-6 and increase in IL-10. Though we did not detect any significant differences in the intestine histology and the purinergic system enzymes, the consumption of α-linolenic acid appears to contribute to the inflammatory and hepatic modulation of animals compared with a diet rich in saturated FAs and or unbalanced in n-6/n-3 PUFAs, inferring possible use in treatment of metabolic disorders associated with obesity and cardiovascular diseases.


Assuntos
Interleucina-10/metabolismo , Interleucina-6/metabolismo , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Ácido alfa-Linoleico/farmacologia , Tecido Adiposo , Animais , Ingestão de Alimentos , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-10/genética , Interleucina-6/genética , Óleo de Semente do Linho/administração & dosagem , Óleo de Semente do Linho/química , Masculino , Valor Nutritivo , Distribuição Aleatória , Ratos , Ratos Wistar , Óleo de Gergelim/administração & dosagem , Óleo de Gergelim/química
13.
Food Funct ; 10(12): 8137-8148, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31746883

RESUMO

High fructose (HF) diet-induced liver steatosis is associated with intestinal microbiota dysbiosis. The aim of this study was to assess the modulatory effects of Artemisia sphaerocephala Krash seed polysaccharide (ASKP) on fatty acid metabolism and intestinal microbiota in mice fed with HF water. Administration of HF-fed mice with ASKP prevented fat accumulation and blunted metabolic inflammation and endotoxaemia. ASKP-treated mice displayed improved glucose tolerance and fully exhibited protection against hepatic steatosis. Besides, ASKP was effective in improving the changes in the composition of liver fatty acids via modulating hepatic SREBP-1c, SCD-1, ACC and FAS expressions. 16S rRNA gene sequencing showed that ASKP treatment modified the gut microbial species at the phylum level with a decrease of Firmicutes and a slight increase of Bacteroidetes (p > 0.05). Interestingly, ASKP markedly increased the proportion of the mucin-degrading bacterium Akkermansia at the genus level in HF-fed mice. These findings support the beneficial metabolic effects of ASKP through amelioration of the HF-induced features of liver steatosis, which is associated with health maintenance of the intestinal microecosystem.


Assuntos
Artemisia/química , Microbioma Gastrointestinal/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Extratos Vegetais/administração & dosagem , Polissacarídeos/administração & dosagem , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Frutose/efeitos adversos , Humanos , Intestinos/efeitos dos fármacos , Intestinos/microbiologia , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/microbiologia , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
14.
Nutrients ; 11(11)2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31726714

RESUMO

Background: The high prevalence of non-alcoholic fatty liver disease (NAFLD) observed in Western countries is due to the concurrent epidemics of overweight/obesity and associated metabolic complications, both recognized risk factors. A Western dietary pattern has been associated with weight gain and obesity, and more recently with NAFLD. Methods: This is a baseline cross-sectional analysis of 136 subjects (79 males) enrolled consecutively in the NUTRIATT (NUTRItion and Ac-TiviTy) study. Study subjects had moderate or severe NAFLD diagnosed by using Fibroscan-CAP. Food Frequency Questionnaire was used to obtain information about food intake. Statistical analysis included descriptive statistics and a multivariable logistic regression model. Results: The mean age was 49.58 (±10.18) with a mean BMI of 33.41 (±4.74). A significant inverse relationship was revealed between winter ice-cream intake and NAFLD severity (O.R. 0.65, 95% C.I. 0.95-0.99); chickpeas intake and NAFLD severity (O.R. 0.57, 95% C.I. 0.34-0.97), and not industrial aged-cheeses type (O.R. 0.85, 95% C.I. 0.74-0.98). A statistically significant positive association also emerged between rabbit meat (O.R. 1.23, 95% C.I. 1.01-1.49), industrial type aged cheeses (O.R. 1.17, 95% C.I. 1.01-1.35), milk-based desserts (no winter ice cream) (O.R. 1.11, 95% C.I. 1.01-1.21), fats (O.R. 1.12, 95% C.I. 1.01-1.25), and NAFLD severity. Conclusion: The fresh foods from non-intensive farming and high legume intake that characterize the Mediterranean diet would seem to be beneficial for patients with NAFLD.


Assuntos
Dieta , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Adulto , Estudos Transversais , Dieta/efeitos adversos , Dieta Saudável , Dieta Mediterrânea , Fabaceae , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Valor Nutritivo , Fatores de Proteção , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Comportamento de Redução do Risco , Índice de Gravidade de Doença
15.
Nutrients ; 11(10)2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31640183

RESUMO

Our aim was to investigate whether hot water extract (CLW) of Curcuma longa L. could prevent non-alcoholic fatty liver disease (NAFLD). HepG2 cells were treated with free fatty acid (FFA) mixture (oleic acid: palmitic acid, 2:1) for 24 h to stimulate in vitro fatty liver. In addition, C57BL/6 mice were fed 60 kcal% high-fat (HF) diet for eight weeks to induce fatty liver in vivo. Intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) productions were increased by FFA and HF-diet, but supplementation with CLW significantly decreased these levels. CLW treatment ameliorated antioxidant activities that were suppressed by exposure to the FFA and HF-diet. Cluster of differentiation 36 (CD36) and fatty acid transport proteins (FATP2 and FATP5) were increased in HF-diet groups, while CLW suppressed their expression levels. Moreover, sterol regulatory element-binding protein-1c (SREBP-1c), acetyl-coenzyme A carboxylase (ACC), and fatty acid synthase (FAS) expression levels were down-regulated in the CLW groups compared to HF-diet groups. On the other hand, 5' adenosine monophosphate-activated protein kinase (AMPK), Peroxisome proliferator-activated receptor alpha (PPAR-α), and carnitine palmitoyltransferase 1 (CPT-1) expressions were up-regulated in the CLW groups. HF-diet fed mice showed high hepatic triglycerides (TG) content compared to the normal diet mice. However, the administration of CLW restored the hepatic TG level, indicating an inhibitory effect against lipid accumulation by CLW. These results suggest that CLW could be a potentially useful agent for the prevention of NAFLD through modulating fatty acid uptake.


Assuntos
Curcuma/química , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Extratos Vegetais/administração & dosagem , Animais , Antioxidantes/análise , Biomarcadores/sangue , Dieta Hiperlipídica , Ácidos Graxos/metabolismo , Ácidos Graxos não Esterificados/farmacologia , Células Hep G2 , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo , RNA Mensageiro/análise , Espécies Reativas de Oxigênio/metabolismo
16.
Int J Mol Sci ; 20(21)2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31653116

RESUMO

: Non-alcoholic fatty liver disease (NAFLD) is a major public health problem in many countries. In this study, the ability of Grifola frondosa heteropolysaccharide (GFP) to ameliorate NAFLD was investigated in rats fed a high-fat diet (HFD). The molecular mechanisms modulating the expression of specific gene members related to lipid synthesis and conversion, cholesterol metabolism, and inflammation pathways were determined. The components of the intestinal microflora in rats were analyzed by high-throughput next-generation 16S rRNA gene sequencing. Supplementation with GFP significantly increased the proportions of Allobaculum, Bacteroides, and Bifidobacterium and decreased the proportions of Acetatifactor, Alistipes, Flavonifractor, Paraprevotella, and Oscillibacter. In addition, Alistipes, Flavonifractor, and Oscillibacter were shown to be significant cecal microbiota according to the Spearman's correlation test between the gut microbiota and biomedical assays (|r| > 0.7). Histological analysis and biomedical assays showed that GFP treatments could significantly protect against NAFLD. In addition, Alistipes, Flavonifractor, and Oscillibacter may play vital roles in the prevention of NAFLD. These results suggest that GFP could be used as a functional material to regulate the gut microbiota of NAFLD individuals.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Grifola/metabolismo , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Polissacarídeos/farmacologia , Animais , Bacteroides/genética , Bacteroides/isolamento & purificação , Bacteroidetes/genética , Bacteroidetes/isolamento & purificação , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/microbiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Polissacarídeos/uso terapêutico , RNA Ribossômico 16S/metabolismo , Ratos , Ratos Wistar , Esteroide 12-alfa-Hidroxilase/genética , Esteroide 12-alfa-Hidroxilase/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo
17.
EMBO Mol Med ; 11(10): e10124, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31595673

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is strongly associated with obesity and may progress to non-alcoholic steatohepatitis (NASH) and liver fibrosis. The deficit of pharmacological therapies for the latter mainly results from an incomplete understanding of involved pathological mechanisms. Herein, we identify apoptosis signal-regulating kinase 1 (ASK1) as a suppressor of NASH and fibrosis formation. High-fat diet-fed and aged chow-fed liver-specific ASK1-knockout mice develop a higher degree of hepatic steatosis, inflammation, and fibrosis compared to controls. In addition, pharmacological inhibition of ASK1 increased hepatic lipid accumulation in wild-type mice. In line, liver-specific ASK1 overexpression protected mice from the development of high-fat diet-induced hepatic steatosis and carbon tetrachloride-induced fibrosis. Mechanistically, ASK1 depletion blunts autophagy, thereby enhancing lipid droplet accumulation and liver fibrosis. In human livers of lean and obese subjects, ASK1 expression correlated negatively with liver fat content and NASH scores, but positively with markers for autophagy. Taken together, ASK1 may be a novel therapeutic target to tackle NAFLD and liver fibrosis.


Assuntos
Cirrose Hepática/fisiopatologia , MAP Quinase Quinase Quinase 5/metabolismo , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Humanos , Cirrose Hepática/prevenção & controle , MAP Quinase Quinase Quinase 5/deficiência , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/prevenção & controle
18.
Yakugaku Zasshi ; 139(9): 1169-1175, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31474633

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is characterized by the pathological accumulation of fat in the liver in the absence of any other disease related to liver steatosis, which includes a wide spectrum ranging from mild asymptomatic fatty liver to nonalcoholic steatohepatitis (NASH) and cirrhosis. However, the pathogenesis of NASH has not been established. In this study, we investigated the involvement of the G-protein-coupled receptor 120/free fatty acid receptor 4 (GPR120/FFAR4) in the pathogenesis of NASH. Mice fed a 0.1% methionine- and choline-deficient l-amino acid-defined, high-fat (CDAHF) diet showed a significant increase in plasma aspartate aminotransferase and alanine aminotransferase levels, fatty deposition, inflammatory cell infiltration, and slight fibrosis. Docosahexanoic acid (DHA, a GPR120/FFAR4 agonist) suppressed the inflammatory cytokines in hepatic tissues and prevented liver fibrosis. On the other hand, GPR120/FFAR4-deficient CDAHF-fed mice showed increments in the number of hepatic crown-like structures and immunoreactivity to F4/80-positive cells compared with wild-type mice. Furthermore, the levels of hepatic TNF-α mRNA expression increased in GPR120-deficient mice. These findings suggest that the GPR120/FFAR4-mediating system could be a key signaling pathway to prevent the development of NASH. In this review, we describe our recent data showing that GPR120/FFAR4 could be a therapeutic target in NASH/NAFLD.


Assuntos
Ácidos Docosa-Hexaenoicos/uso terapêutico , Terapia de Alvo Molecular , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/fisiologia , Animais , Ácidos Docosa-Hexaenoicos/farmacologia , Humanos , Camundongos , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
19.
Food Funct ; 10(9): 6170-6183, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31501836

RESUMO

High-fat-diet (HFD) feeding is associated with liver oxidative stress (OS), n-3 long-chain polyunsaturated fatty acid (n-3 LCPUFA) depletion, hepatic steatosis and mitochondrial dysfunction. Our hypothesis is that the HFD-induced liver injury can be attenuated by the combined supplementation of n-3 LCPUFA eicosapentaenoic acid (EPA) and the antioxidant hydroxytyrosol (HT). The C57BL/6J mice were administered an HFD (60% fat, 20% protein, 20% carbohydrates) or control diet (CD; 10% fat, 20% protein, 70% carbohydrates), with or without EPA (50 mg kg-1 day-1), HT (5 mg kg-1 day-1), or EPA + HT (50 and 5 mg kg-1 day-1, respectively) for 12 weeks. We measured the body and liver weights and dietary and energy intakes along with liver histology, FA composition, steatosis score and associated transcription factors, mitochondrial functions and metabolic factors related to energy sensing through the AMP-activated protein kinase (AMPK) and PPAR-γ coactivator-1α (PGC-1α) cascade. It was found that the HFD significantly induced liver steatosis, with a 66% depletion of n-3 LCPUFAs and a 100% increase in n-6/n-3 LCPUFA ratio as compared to the case of CD (p < 0.05). These changes were concomitant with (i) a 95% higher lipogenic and 70% lower FA oxidation signaling, (ii) a 40% diminution in mitochondrial respiratory capacity and (iii) a 56% lower ATP content. HFD-induced liver steatosis was also associated with (iv) a depressed mRNA expression of AMPK-PGC-1α signaling components, nuclear respiratory factor-2 (NRF-2) and ß-ATP synthase. These HFD effects were significantly attenuated by the combined EPA + HT supplementation in an additive manner. These results suggested that EPA and HT co-administration partly prevented HFD-induced liver steatosis, thus strengthening the importance of combined interventions in hepatoprotection in non-alcoholic fatty liver disease.


Assuntos
Ácido Eicosapentaenoico/administração & dosagem , Metabolismo Energético/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Álcool Feniletílico/análogos & derivados , Trifosfato de Adenosina/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais/análise , Sinergismo Farmacológico , Ácidos Graxos Ômega-3/metabolismo , Fator de Transcrição de Proteínas de Ligação GA/genética , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Humanos , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Álcool Feniletílico/administração & dosagem
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