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1.
Life Sci ; 258: 118240, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32781072

RESUMO

As a dicarboxylic acid with the structural formula HOOCCH (OH) COOH, tartronic acid is considered as an inhibitor of the transformation of carbohydrates into fat under fat-deficient diet conditions. However, the effect of tartronic acid on lipogenesis under high-fat diet conditions has yet to be established. In this work, we investigated the regulatory role of tartronic acid in lipogenesis in 3T3-L1 adipocytes and C57BL/6J mice. The results confirmed that tartronic acid promoted weight gain (without affecting food intake) and induced adipocyte hypertrophy in epididymal white adipose tissue and lipid accumulation in the livers of high-fat diet-induced obese mice. In vitro, tartronic acid promoted 3T3-L1 adipocyte differentiation by increasing the protein expression of FABP-4, PPARγ and SREBP-1. Moreover, the contents of both acetyl-CoA and malonyl-CoA were significantly upregulated by treatment with tartronic acid, while the protein expression of CPT-1ß were inhibited. In summary, we proved that tartronic acid promotes lipogenesis by serving as substrates for fatty acid synthesis and inhibiting CPT-1ß, providing a new perspective for the study of tartronic acid.


Assuntos
Acetilcoenzima A/biossíntese , Carnitina O-Palmitoiltransferase/antagonistas & inibidores , Lipogênese/efeitos dos fármacos , Malonil Coenzima A/biossíntese , Tartronatos/farmacologia , Regulação para Cima/efeitos dos fármacos , Células 3T3-L1 , Animais , Carnitina O-Palmitoiltransferase/metabolismo , Dieta Hiperlipídica/efeitos adversos , Lipogênese/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Regulação para Cima/fisiologia
2.
J Food Sci ; 85(7): 2198-2206, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32614078

RESUMO

The hemolytic property discourages the development of sea cucumber saponins on alleviating lipids metabolism disturbance. The hemolytic activity of saponins has been reported to be highly correlative to their chemical structures. The aim of this study was to reduce the hemolytic activity of sea cucumber-derived saponins echinoside A (EA) and simultaneously remain its effect on alleviating non-alcoholic fatty liver disease (NAFLD) by structural modifications. Administration with EA and its derivatives for 8 weeks remarkably mitigated orotic acid-induced NAFLD via inhibiting the activities and mRNA expressions of enzymes involved in lipogenesis, enhancing the activities and expressions of enzymes related to hepatic lipolysis in a rat model. Importantly, aglycone exhibited a distinct advantage in stimulating hepatic lipolysis compared with EA and dsEA, meanwhile possessed lowest hemolytic activity. This study may provide the theoretical basis to strengthen the application of sea cucumber saponins as food supplements and/or functional ingredients.


Assuntos
Holoturina/análogos & derivados , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Pepinos-do-Mar/química , Animais , Holoturina/administração & dosagem , Holoturina/química , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Ratos , Ratos Wistar , Saponinas/administração & dosagem , Saponinas/química
3.
Chemosphere ; 258: 127360, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32554016

RESUMO

Environmental pollutants are thought to be a risk factor for the prevalence of hepatic steatosis. Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous, and human exposure is inevitable. In the present study, phenanthrene (Phe) was used as a representative PAH to investigate the effects of in utero exposure to PAH on hepatic lipid metabolism and the toxicological mechanism involved. Pregnant mice (C57BL/6J) were orally administered Phe (0, 60, 600 and 6000 µg kg-1 body weight) once every 3 days with 6 doses in total. F1 female mice aged 125 days showed significantly elevated hepatic lipid levels in the liver. The protein expression of hepatic peroxisome proliferator-activated receptors (PPARß and PPARγ) and retinoid X receptors (RXRs) was upregulated; the transcription of genes related to lipogenesis, such as srebp1 (encoding sterol regulatory element binding proteins), acca (acetyl-CoA carboxylase), fasn (fatty acid synthase) and pcsk9 (proprotein convertase subtilisin/kexin type 9), showed an upregulation, while the mRNA levels of the lipolysis gene lcat (encoding lecithin cholesterol acyl transferase) were downregulated. These results could be responsible for lipid accumulation. The promoter methylation levels of pparγ were reduced and were the lowest in the 600 µg kg-1 group, and the promoter methylation levels of lcat were significantly increased in all the Phe treatments. These changes were matched with the alterations in their mRNA levels, suggesting that prenatal Phe exposure could induce abnormal lipid metabolism in later life via epigenetic modification.


Assuntos
Poluentes Ambientais/toxicidade , Epigênese Genética/efeitos dos fármacos , Fígado Gorduroso/virologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fenantrenos/toxicidade , Efeitos Tardios da Exposição Pré-Natal/virologia , Idoso de 80 Anos ou mais , Animais , Fígado Gorduroso/embriologia , Fígado Gorduroso/metabolismo , Feminino , Humanos , Metabolismo dos Lipídeos/genética , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Lipólise/efeitos dos fármacos , Lipólise/genética , Fígado/efeitos dos fármacos , Fígado/crescimento & desenvolvimento , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Transcrição Genética/genética
4.
Viruses ; 12(6)2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32532085

RESUMO

The ongoing Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) signals an urgent need for an expansion in treatment options. In this study, we investigated the anti-SARS-CoV-2 activities of 22 antiviral agents with known broad-spectrum antiviral activities against coronaviruses and/or other viruses. They were first evaluated in our primary screening in VeroE6 cells and then the most potent anti-SARS-CoV-2 antiviral agents were further evaluated using viral antigen expression, viral load reduction, and plaque reduction assays. In addition to remdesivir, lopinavir, and chloroquine, our primary screening additionally identified types I and II recombinant interferons, 25-hydroxycholesterol, and AM580 as the most potent anti-SARS-CoV-2 agents among the 22 antiviral agents. Betaferon (interferon-ß1b) exhibited the most potent anti-SARS-CoV-2 activity in viral antigen expression, viral load reduction, and plaque reduction assays among the recombinant interferons. The lipogenesis modulators 25-hydroxycholesterol and AM580 exhibited EC50 at low micromolar levels and selectivity indices of >10.0. Combinational use of these host-based antiviral agents with virus-based antivirals to target different processes of the SARS-CoV-2 replication cycle should be evaluated in animal models and/or clinical trials.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Animais , Antígenos Virais/imunologia , Betacoronavirus/imunologia , Betacoronavirus/metabolismo , Chlorocebus aethiops , Infecções por Coronavirus/virologia , Humanos , Interferons/metabolismo , Lipogênese/efeitos dos fármacos , Pandemias , Pneumonia Viral/virologia , Transdução de Sinais/efeitos dos fármacos , Células Vero , Carga Viral/efeitos dos fármacos , Ensaio de Placa Viral , Replicação Viral/efeitos dos fármacos
5.
Life Sci ; 256: 118012, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32593710

RESUMO

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


Assuntos
Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Fenóis/toxicidade , Adiposidade/efeitos dos fármacos , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Progressão da Doença , Feminino , Glucose/metabolismo , Resistência à Insulina , Lipogênese/efeitos dos fármacos , Camundongos , Hepatopatia Gordurosa não Alcoólica/patologia , Ovariectomia
6.
J Food Sci ; 85(7): 2216-2226, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32579753

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease that is closely related to metabolic syndrome. We investigated the effect of a Psoralea corylifolia L. (PC) seeds extract (PCE) on NAFLD. PC seeds were extracted using different ethanol concentrations to produce five extracts, and the 70% ethanol PCE, which had the highest phenolic content, was used in subsequent in vitro and in vivo experiments. The inhibitory effect of PCE on hepatic steatosis was estimated using HepG2 cells treated with oleic acid (OA). In addition, an in vivo NAFLD model was established using high-fat diet (HFD)-induced obese C57BL/6 mice. Obesity was induced in mice over 14 weeks. PCE (100 or 200 mg/kg/day) was administered orally to mice after 8 weeks of the 14-week treatment period for 6 weeks. PCE suppressed lipid accumulation in OA-treated HepG2 cells. PCE ameliorated the antioxidant activity suppressions induced by the HFD. In addition, both PCE100 and PCE200 groups reduced lipid accumulation and the expression levels of inflammatory proteins as compared with HFD group. PCE administration significantly attenuated hepatic steatosis in liver tissues by decreasing the expression of lipogenic protein sterol regulatory element binding protein 1-c (SREBP-1c) and its downstream protein fatty acid synthase (FAS) in HFD-fed mice and in OA-treated HepG2 cells. Furthermore, PCE administration increased the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase. These results suggest that PCE could be used as a functional material to prevent or ameliorate NAFLD by inhibiting lipid accumulation in liver. PRACTICAL APPLICATION: Psoralea corylifolia L. is rich in polyphenol and other phytochemicals. In this study, we identified the beneficial effects of Psoralea corylifolia L. extract on hepatic steatosis in oleic-acid-induced HepG2 cells and high-fat diet-fed mice. The result of this study will provide the evidence that a Psoralea corylifolia L. extract has potential use as a functional material for the prevention and amelioration of nonalcoholic fatty liver disease.


Assuntos
Ácidos Graxos não Esterificados/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Extratos Vegetais/administração & dosagem , Psoralea/química , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Células Hep G2 , Humanos , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
7.
Metabolism ; 107: 154222, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32246987

RESUMO

Fructose over-consumption contributes to the development of liver steatosis in part by stimulating ChREBPα-driven de novo lipogenesis. However, the mechanisms by which fructose activates ChREBP pathway remain largely undefined. Here we performed affinity purification of ChREBPα followed by mass spectrometry and identified DDB1 as a novel interaction protein of ChREBPα in the presence of fructose. Depletion and overexpression of Ddb1 showed opposite effects on the ChREBPα stability in hepatocytes. We next tested the impact of hepatic Ddb1 deficiency on the fructose-induced ChREBP pathway. After 3-week high-fructose diet feeding, both Ddb1 liver-specific knockout and AAV-TBG-Cre-injected Ddb1flox/flox mice showed significantly reduced ChREBPα, lipogenic enzymes, as well as triglycerides in the liver. Mechanistically, DDB1 stabilizes ChREBPα through CRY1, a known ubiquitination target of DDB1 E3 ligase. Finally, overexpression of a degradation-resistant CRY1 mutant (CRY1-585KA) reduces ChREBPα and its target genes in the mouse liver following high-fructose diet feeding. Our data revealed DDB1 as an intracellular sensor of fructose intake to promote hepatic de novo lipogenesis and liver steatosis by stabilizing ChREBPα in a CRY1-dependent manner.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Criptocromos/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Carboidratos da Dieta/farmacologia , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/genética , Frutose/farmacologia , Proteínas Imediatamente Precoces/metabolismo , Proteínas de Membrana/metabolismo , Animais , Hepatócitos/metabolismo , Proteínas Imediatamente Precoces/genética , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação/genética , Cultura Primária de Células , Ubiquitinação
8.
BMC Complement Med Ther ; 20(1): 75, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32143613

RESUMO

BACKGROUND: Various extracts of Hovenia dulcis have been commonly used in Asia for cases of alcohol-related disorders. Fermentation is reported to enhance the level and biological activities of various bio-constituents of plant extracts. Therefore, this study was undertaken to evaluate the effects of fermented H. dulcis extract (FHDE) on ethanol-induced liver injury in mice. METHODS: FHDE was prepared using Bacillus subtilis and Lactobacillus plantarum. The effects of FHDE on ethanol-induced liver injury were evaluated in C57BL/6 N CrSlc mice. A mixed feed preparation containing the fermented extract with and without ethanol was given to mice for 29 days, according to its group. At the end of the experiment, blood and liver samples were collected from all mice in the group. Plasma biochemical analysis and histopathological investigation were performed to evaluate the impacts of treatment on the biomarkers of hepatic damage and inflammatory changes. Besides, the expression of genes that regulate the activities of enzymes associated with alcohol metabolism, antioxidant activity, and fatty acid oxidation was assessed using a quantitative real-time polymerase chain reaction. Moreover, the amino acid contents and the active ingredients of the extract were evaluated before and after fermentation. RESULTS: Fermentation resulted in a marked increase and decrease in the amount of Gamma-Amino-n-butyric acid (GABA) and glutamic acid, respectively. FHDE enhanced the body weight gain of mice compared to ethanol. Besides, plasma levels of triglyceride, low-density lipoprotein, the activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were significantly (P < 0.05) reduced in the FHDE-treated groups relative to the ethanol-treated control. FHDE upregulated the expression of genes associated with enzymes involved in alcohol dehydrogenation (Adh1 and Aldh2), antioxidant activity (SOD and CAT), and fatty acid oxidation (PPAR-α and PGC-1α). However, the expressions of Cytochrome peroxidase Cyp2E1 and genes related to lipogenesis (SREBP-1c, FAS, SCD-1, and ACC) were significantly (P < 0.05) downregulated following treatment with the FHDE. Histopathological investigation demonstrated a slight degree of inflammatory cell infiltration and occasional fatty changes in the FHDE-treated groups. CONCLUSION: The GABA-enriched fermented H. dulcis extract prevented ethanol-induced hepatic damage by enhancing the antioxidant defense system, fatty acid oxidation, and reducing lipogenesis.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Extratos Vegetais/farmacologia , Rhamnaceae/química , Ácido gama-Aminobutírico/farmacologia , Animais , Cromatografia , Modelos Animais de Doenças , Etanol/efeitos adversos , Fermentação , Lipogênese/efeitos dos fármacos , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , República da Coreia
9.
Nature ; 579(7800): 586-591, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32214246

RESUMO

Consumption of fructose has risen markedly in recent decades owing to the use of sucrose and high-fructose corn syrup in beverages and processed foods1, and this has contributed to increasing rates of obesity and non-alcoholic fatty liver disease2-4. Fructose intake triggers de novo lipogenesis in the liver4-6, in which carbon precursors of acetyl-CoA are converted into fatty acids. The ATP citrate lyase (ACLY) enzyme cleaves cytosolic citrate to generate acetyl-CoA, and is upregulated after consumption of carbohydrates7. Clinical trials are currently pursuing the inhibition of ACLY as a treatment for metabolic diseases8. However, the route from dietary fructose to hepatic acetyl-CoA and lipids remains unknown. Here, using in vivo isotope tracing, we show that liver-specific deletion of Acly in mice is unable to suppress fructose-induced lipogenesis. Dietary fructose is converted to acetate by the gut microbiota9, and this supplies lipogenic acetyl-CoA independently of ACLY10. Depletion of the microbiota or silencing of hepatic ACSS2, which generates acetyl-CoA from acetate, potently suppresses the conversion of bolus fructose into hepatic acetyl-CoA and fatty acids. When fructose is consumed more gradually to facilitate its absorption in the small intestine, both citrate cleavage in hepatocytes and microorganism-derived acetate contribute to lipogenesis. By contrast, the lipogenic transcriptional program is activated in response to fructose in a manner that is independent of acetyl-CoA metabolism. These data reveal a two-pronged mechanism that regulates hepatic lipogenesis, in which fructolysis within hepatocytes provides a signal to promote the expression of lipogenic genes, and the generation of microbial acetate feeds lipogenic pools of acetyl-CoA.


Assuntos
Acetatos/metabolismo , Açúcares da Dieta/metabolismo , Frutose/metabolismo , Microbioma Gastrointestinal/fisiologia , Lipogênese , Fígado/metabolismo , ATP Citrato (pro-S)-Liase/deficiência , ATP Citrato (pro-S)-Liase/genética , ATP Citrato (pro-S)-Liase/metabolismo , Acetato-CoA Ligase/deficiência , Acetato-CoA Ligase/genética , Acetato-CoA Ligase/metabolismo , Acetilcoenzima A/metabolismo , Animais , Ácido Cítrico/metabolismo , Açúcares da Dieta/administração & dosagem , Açúcares da Dieta/farmacologia , Ácidos Graxos/metabolismo , Frutose/administração & dosagem , Frutose/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Marcação por Isótopo , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Camundongos , Especificidade por Substrato
10.
J Agric Food Chem ; 68(14): 4215-4226, 2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32181656

RESUMO

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


Assuntos
Dieta Hiperlipídica/efeitos adversos , Ginsenosídeos/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Sirtuína 1/metabolismo , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Fígado , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Ácido Oleico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ácido Palmítico/metabolismo
11.
Br J Nutr ; 124(4): 363-373, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32189604

RESUMO

Barramundi (Lates calcarifer) are a highly valued aquaculture species, and, as obligate carnivores, they have a demonstrated preference for dietary protein over lipid or starch to fuel energetic growth demands. In order to investigate how carnivorous fish regulate nutritional cues, we examined the metabolic effects of feeding two isoenergetic diets that contained different proportions of digestible protein or starch energy. Fish fed a high proportion of dietary starch energy had a higher proportion of liver SFA, but showed no change in plasma glucose levels, and few changes in the expression of genes regulating key hepatic metabolic pathways. Decreased activation of the mammalian target of rapamycin growth signalling cascade was consistent with decreased growth performance values. The fractional synthetic rate (lipogenesis), measured by TAG 2H-enrichment using 2H NMR, was significantly higher in barramundi fed with the starch diet compared with the protein diet (0·6 (se 0·1) v. 0·4 (se 0·1) % per d, respectively). Hepatic TAG-bound glycerol synthetic rates were much higher than other closely related fish such as sea bass, but were not significantly different (starch, 2·8 (se 0·3) v. protein, 3·4 (se 0·3) % per d), highlighting the role of glycerol as a metabolic intermediary and high TAG-FA cycling in barramundi. Overall, dietary starch significantly increased hepatic TAG through increased lipogenesis. Compared with other fish, barramundi possess a unique mechanism to metabolise dietary carbohydrates and this knowledge may define ways to improve performance of advanced formulated feeds.


Assuntos
Bass/metabolismo , Dieta/veterinária , Lipogênese/efeitos dos fármacos , Amido/farmacologia , Fenômenos Fisiológicos da Nutrição Animal , Animais , Proteínas na Dieta/farmacologia , Fígado/metabolismo
12.
J Med Food ; 23(3): 215-223, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32191576

RESUMO

Anti-obesity activities of Korean red ginseng saponin fraction (RGS) and/or Glycyrrhiza glabra L. extract (GG) were investigated in 3T3-L1 adipocytes and high-fat diet-induced C57BL/6J obese mice. RGS and GG extracts were mixed at a mass ratio of 3:1 (SG31), 1:1 (SG11), or 1:3 (SG13). SG31 showed the highest anti-obesity activity among the three different mass ratios of RGS and GG extracts. SG31 showed higher inhibition efficiency on triglyceride (TG) accumulation than either single extract in 3T3-L1 adipocytes and without any cytotoxicity. It also decreases the expression of adipogenic and lipogenic genes such as C/EBPα and SREBP-1c (sterol regulatory element-binding protein 1c). In the obese induced mouse model, SG31 significantly reduced white adipose tissue weight and body weight, attenuated dyslipidemia, and decreased serum TG levels. In some indices, the activity of SG31 was even higher compared with Garcinia Cambogia water extract, a positive control. The possible mechanism by which SG31 causes the above results was by activating the AMP-activated protein kinase (AMPK) pathway and stimulating the secretion of adiponectin in adipose tissue to regulate energy metabolism balance, inhibit TG formation, and promote ß-oxidation of fatty acids. Therefore, SG31 may have efficacy as an anti-obesity functional food or raw material if the results can be confirmed in human studies.


Assuntos
Adipócitos/efeitos dos fármacos , Fármacos Antiobesidade/administração & dosagem , Glycyrrhiza/química , Obesidade/tratamento farmacológico , Panax/química , Extratos Vegetais/administração & dosagem , Células 3T3-L1 , Adipócitos/metabolismo , Animais , Fármacos Antiobesidade/análise , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Humanos , Lipogênese/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/genética , Obesidade/metabolismo , Obesidade/fisiopatologia , PPAR gama/genética , PPAR gama/metabolismo , Extratos Vegetais/análise , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/sangue
13.
J Med Food ; 23(3): 233-241, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32191577

RESUMO

Eriocitrin (EC) is an abundant flavonoid in lemons, which is known as a strong antioxidant agent. This study investigated the biological and molecular mechanisms underlying the anti-obesity effect of EC in high-fat diet (HFD)-fed obese mice. C57BL/6N mice were fed an HFD (40 kcal% fat) with or without 0.005% (w/w) EC for 16 weeks. Dietary EC improved adiposity by increasing adipocyte fatty acid (FA) oxidation, energy expenditure, and mRNA expression of thermogenesis-related genes in brown adipose tissue (BAT) and skeletal muscle, whereas it also decreased lipogenesis-related gene expression in white adipose tissue. In addition to adiposity, EC prevented hepatic steatosis by diminishing lipogenesis while enhancing FA oxidation in the liver and fecal lipid excretion, which was linked to attenuation of hyperlipidemia. Moreover, EC improved insulin sensitivity by decreasing hepatic gluconeogenesis and proinflammatory responses. These findings indicate that EC may protect against diet-induced adiposity and related metabolic disorders by controlling thermogenesis of BAT and skeletal muscle, FA oxidation, lipogenesis, fecal lipid excretion, glucose utilization, and gluconeogenesis.


Assuntos
Adiposidade/efeitos dos fármacos , Flavanonas/administração & dosagem , Obesidade/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/fisiopatologia , Animais , Citrus/química , Dieta Hiperlipídica , Lipogênese/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Fitoterapia , Termogênese/efeitos dos fármacos
14.
Nat Commun ; 11(1): 796, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034158

RESUMO

Fatty acid and triglyceride synthesis increases greatly in response to feeding and insulin. This lipogenic induction involves coordinate transcriptional activation of various enzymes in lipogenic pathway, including fatty acid synthase and glycerol-3-phosphate acyltransferase. Here, we show that JMJD1C is a specific histone demethylase for lipogenic gene transcription in liver. In response to feeding/insulin, JMJD1C is phosphorylated at T505 by mTOR complex to allow direct interaction with USF-1 for recruitment to lipogenic promoter regions. Thus, by demethylating H3K9me2, JMJD1C alters chromatin accessibility to allow transcription. Consequently, JMJD1C promotes lipogenesis in vivo to increase hepatic and plasma triglyceride levels, showing its role in metabolic adaption for activation of the lipogenic program in response to feeding/insulin, and its contribution to development of hepatosteatosis resulting in insulin resistance.


Assuntos
Histona Desmetilases com o Domínio Jumonji/metabolismo , Lipogênese/fisiologia , Oxirredutases N-Desmetilantes/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Ingestão de Alimentos/genética , Ingestão de Alimentos/fisiologia , Feminino , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Células Hep G2 , Histonas/metabolismo , Humanos , Insulina/metabolismo , Insulina/farmacologia , Resistência à Insulina , Histona Desmetilases com o Domínio Jumonji/genética , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Lisina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxirredutases N-Desmetilantes/genética , Fosforilação , Regiões Promotoras Genéticas , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Fatores Estimuladores Upstream/metabolismo
15.
Biochem Biophys Res Commun ; 524(3): 716-722, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32035613

RESUMO

MicroRNAs are well acknowledged as key mediators in the development of chronic metabolic diseases, including NAFLD. However, their roles in hepatic lipid metabolism and fatty liver still remain well elucidated. Here, we found that miR-103 represses de novo lipogenesis (DNL) and dampens the development of obesity/diet-induced fatty liver through targeting at Fasn and Scd1 in mouse liver. miR-103, robustly amplified in obese livers, inhibits the expression of Fasn and Scd1 via directly interacting with their mRNA 3' untranslated regions. Upregulated miR-103 sufficiently reduces the expression of Fasn and Scd1 and blocks the lipid accumulation in oleate-incubated hepatocytes. Furthermore, specifically overexpressing miR-103 in mouse liver by adenovirus significantly inhibits hepatic DNL to repress HCD-promoted hepatic lipid contents as well as NAFLD development. Meanwhile, enforced expression of hepatic miR-103 also alleviates obesity-associated fatty liver via reducing Fasn and Scd1 in db/db mice. Together, our study reveals a critical role of miR-103 in lipid homeostasis of liver and pathogenesis of NAFLD.


Assuntos
Ácido Graxo Sintases/metabolismo , Lipogênese/genética , Fígado/metabolismo , Fígado/patologia , MicroRNAs/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Estearoil-CoA Dessaturase/metabolismo , Animais , Sequência de Bases , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Lipogênese/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Obesos , MicroRNAs/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Ácido Oleico/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Estearoil-CoA Dessaturase/genética
16.
Biochem Biophys Res Commun ; 525(2): 455-461, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32107002

RESUMO

Metabolic syndrome is defined by hyperlipidemia and cardiovascular complications. We have examined whether inhibition of glycosphingolipid synthesis can interfere with metabolic syndrome in a male mouse model of type II diabetes (db/db). The db/db and control mice (C57/BL6) (n = 6) fed chow for 30 weeks received vehicle (5% Tween-80 in PBS; 100 µl), or a biopolymer-encapsulated D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (BPD) glycosphingolipid synthesis inhibitor daily via oral gavage for 6 weeks. Echocardiography revealed increased Ao-IMT in db/db mice compared to control. However, BPD decreased Ao-IMT, monohexosylceramide and dihexosylceramide, LDL, triglycerides, glucose, and raised HDL levels in db/db mice. This was due to increased gene expression of HMG-CoA reductase, LDLr, SREBP2, and bile acids: Cy7-a hydroxylase, LXR and FXR, lipoprotein lipase, VLDL receptor and PPAR. Treatment also increased the expression of superoxide dismutase-II to reduce the pro-oxidant status in these mice. We observed that decreased cholesterol levels correlated with decreased cholesterol sensing proteins e.g. NPC1 gene/protein expression and mammalian target of rapamycin (mTORC-1) and reduced body weight. Thus, glycosphingolipid synthesis inhibition is a novel approach to manage metabolic syndrome and reduce body weight in diabetic mice and with potential applications in humans.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Glicoesfingolipídeos/metabolismo , Lipogênese/efeitos dos fármacos , Síndrome Metabólica/tratamento farmacológico , Morfolinas/uso terapêutico , Animais , Fármacos Antiobesidade/uso terapêutico , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Masculino , Síndrome Metabólica/complicações , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
17.
Artigo em Inglês | MEDLINE | ID: mdl-32045698

RESUMO

The exact role of VD deficiency in the development of non-alcoholic fatty liver disease (NAFLD) remains unknown. In this study, we induced VD deficiency by feeding Female Sprague-Dawley rats a VD deficient (VDD) Diet and studied the hepatic changes associated with VD deficiency. Simultaneously, we provided the VDD rats with VD or 8-methoxy psoralen (8-MOP), a suggested vitamin D receptor agonist, to test the reversibility of the hepatic changes. VDD Rats developed borderline non-alcoholic steatohepatitis (NASH) with considerable elevation in hepatic triglycerides, total cholesterol, and malondialdehyde. Furthermore, VD deficiency induced the expression of crucial enzymes and transcription factors involved in denovo lipogenesis, which justified the hepatic lipid accumulation. Insulin receptor signaling was affected by VD deficiency, demonstrated by the elevation in insulin substrate-1 (IRS1) and reduction in insulin substrate-2 (IRS2) signaling. Treatment with VD or 8-MOP attenuated IRS1 signaling and its downstream targets, leading to a decline in de novo lipogenesis, while the elevation in IRS2 expression resulted in the nuclear exclusion of forkhead box O1 (FoxO1) and diminished gluconeogenesis, a vital source of acetyl-CoA for de novo lipogenesis. Moreover, 8-MOP and Calcipotriol modulated insulin signaling in human hepatocyte cell line L02, which highlighted the crucial role of VD in the regulation of hepatic lipid contents in rats and humans. Silencing of the vitamin D receptor expression in L02 diminished the inhibitory effect of Calcipotriol and 8-MOP on fatty acid synthase and acetyl- CoA carboxylase 1 and provided the evidence that 8-MOP actions mediated via vitamin D receptor.


Assuntos
Proteínas Substratos do Receptor de Insulina/metabolismo , Metoxaleno/farmacologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Deficiência de Vitamina D/complicações , Ração Animal , Animais , Calcitriol/administração & dosagem , Calcitriol/análogos & derivados , Linhagem Celular , Feminino , Técnicas de Silenciamento de Genes , Gluconeogênese , Humanos , Insulina/metabolismo , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Metoxaleno/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Vitamina D/administração & dosagem , Vitamina D/metabolismo , Deficiência de Vitamina D/metabolismo
18.
Biochim Biophys Acta Mol Basis Dis ; 1866(5): 165721, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32057942

RESUMO

Genomics has contributed to the treatment of a fraction of cancer patients. However, there is a need to profile the proteins that define the phenotype of cancer and its pathogenesis. The reprogramming of metabolism is a major trait of the cancer phenotype with great potential for prognosis and targeted therapy. This review overviews the major changes reported in the steady-state levels of proteins of metabolism in primary carcinomas, paying attention to those enzymes that correlate with patients' survival. The upregulation of enzymes of glycolysis, pentose phosphate pathway, lipogenesis, glutaminolysis and the antioxidant defense is concurrent with the downregulation of mitochondrial proteins involved in oxidative phosphorylation, emphasizing the potential of mitochondrial metabolism as a promising therapeutic target in cancer. We stress that high-throughput quantitative expression profiling of differentially expressed proteins in large cohorts of carcinomas paired with normal tissues will accelerate translation of metabolism to a successful personalized medicine in cancer.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Carcinoma/patologia , Metabolismo Energético/efeitos dos fármacos , Mitocôndrias/enzimologia , Animais , Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinoma/tratamento farmacológico , Carcinoma/genética , Carcinoma/mortalidade , Modelos Animais de Doenças , Progressão da Doença , Regulação para Baixo , Metabolismo Energético/genética , Regulação Neoplásica da Expressão Gênica , Glicólise/efeitos dos fármacos , Glicólise/genética , Humanos , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Mitocôndrias/efeitos dos fármacos , Mutação , Fosforilação Oxidativa/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Prognóstico , Espécies Reativas de Oxigênio/metabolismo , Taxa de Sobrevida , Regulação para Cima
19.
J Dairy Sci ; 103(3): 2255-2263, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31954562

RESUMO

The objective of this study was to investigate the effect of increasing dietary supplementation of crushed sunflower seed (CSS) in the diet of dairy cows on the fatty acid (FA) composition of phospholipids and sphingomyelin in milk, and on mammary transcription of genes that are important for sphingomyelin de novo synthesis. Four groups of 6 cows received diets supplemented with CSS at 0% (control), or 5, 10, or 15% of dry matter for a 5-wk experimental period. Milk samples and mammary biopsies were collected at the end of the experiment. Phospholipid concentration in milk fat decreased linearly with CSS supplementation. Sphingomyelin concentration in milk fat was unaffected by CSS supplementation. Daily yield of phospholipids decreased linearly with CSS supplementation. Daily yield of sphingomyelin was not significantly affected. The CSS supplementation linearly increased the proportion of monounsaturated FA in milk phospholipids. The major isomer incorporated into phospholipids was C18:1 (n-9 cis), which showed a linear increase with CSS supplementation. The C22:0 proportion in sphingomyelin increased linearly with CSS supplementation and constituted between 15.2 to 25.4% of total FA in sphingomyelin. However, CSS supplementation linearly decreased C23:0 sphingomyelin. Mammary transcription of serine palmitoyl transferase, long chain subunit 1 and subunit 2, the rate-limiting enzymes in ceramide synthesis, showed a linear decrease with increasing CSS supplementation. In conclusion, the data showed that dietary supplementation of CSS linearly increased the proportion of unsaturated FA and monounsaturated FA in milk phospholipids with no effect on phospholipid concentration. In addition, CSS supplementation linearly decreased n-3 polyunsaturated fatty acid proportion in sphingomyelin. The results further showed that mammary transcription of important genes for sphingomyelin de novo synthesis is regulated by lipid supplementation.


Assuntos
Bovinos/fisiologia , Suplementos Nutricionais/análise , Ácidos Graxos/química , Helianthus , Lipogênese/efeitos dos fármacos , Leite/química , Fosfolipídeos/química , Esfingomielinas/química , Ração Animal/análise , Animais , Dieta/veterinária , Ácidos Graxos Insaturados/química , Feminino , Lactação , Sementes , Esfingomielinas/biossíntese
20.
Int J Mol Sci ; 21(2)2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31936890

RESUMO

Ergosterol peroxide is a natural compound of the steroid family found in many fungi, and it possesses antioxidant, anti-inflammatory, anticancer and antiviral activities. The anti-obesity activity of several edible and medicinal mushrooms has been reported, but the effect of mushroom-derived ergosterol peroxide on obesity has not been studied. Therefore, we analyzed the effect of ergosterol peroxide on the inhibition of triglyceride synthesis at protein and mRNA levels and differentiation of 3T3-L1 adipocytes. Ergosterol peroxide inhibited lipid droplet synthesis of differentiated 3T3-L1 cells, expression of peroxisome proliferator-activated receptor gamma (PPARγ) and CCAT/enhancer-binding protein alpha (C/EBPα), the major transcription factors of differentiation, and also the expression of sterol regulatory element-binding protein-1c (SREBP-1c), which promotes the activity of PPARγ, resulting in inhibition of differentiation. It further inhibited the expression of fatty acid synthase (FAS), fatty acid translocase (FAT), and acetyl-coenzyme A carboxylase (ACC), which are lipogenic factors. In addition, it inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs) involved in cell proliferation and activation of early differentiation transcription factors in the mitotic clonal expansion (MCE) stage. As a result, ergosterol peroxide significantly inhibited the synthesis of triglycerides and differentiation of 3T3-L1 cells, and is, therefore, a possibile prophylactic and therapeutic agent for obesity and related metabolic diseases.


Assuntos
Adipócitos/metabolismo , Fármacos Antiobesidade/farmacologia , Diferenciação Celular/efeitos dos fármacos , Ergosterol/análogos & derivados , Metabolismo dos Lipídeos/efeitos dos fármacos , Reishi/química , Células 3T3-L1/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Adipocinas , Animais , Fármacos Antiobesidade/uso terapêutico , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Ergosterol/química , Ergosterol/farmacologia , Ergosterol/uso terapêutico , Lipogênese/efeitos dos fármacos , Camundongos , PPAR gama/metabolismo , Fosforilação/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos
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