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1.
Chem Biol Interact ; 311: 108794, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31421115

RESUMO

Acanthoic acid (AA) is a pimaradiene diterpene isolated from Acanthopanax koreanum Nakai (Araliaceae), with anti-inflammatory and hepatic-protective effects. The present study intended to reveal the effect and mechanism of AA on nonalcoholic fatty liver disease (NAFLD) associated with lipid accumulation by activating Farnesoid X receptor (FXR) and liver X receptors (LXRs) signaling. C57BL/6 mice were received a modified Lieber-DeCarli diet with 71% high-fat (L-D) and treated with AA (20 and 40 mg/kg) or equal volume of saline for 12 weeks. The regulation of AA on lipid accumulation was also detected in pro-steatotic stimulated AML12 cells with palmitic acid (PA). When L-D diet-fed mice were treated with AA, loss in body weight, liver index, and liver lipid droplet were observed along with reduced triglyceride (TG) and serum transaminase. Furthermore, AA decreased sterol regulatory element binding protein 1 (SREBP-1) and target genes expression, regulated PPARα and PPARγ expressions, ameliorated hepatic fibrosis markers, enhanced hepatic FXR and LXR, and regulated AMPK-LKB1 and SIRT1 signaling pathway. Moreover, AA attenuated lipid accumulation via FXR and LXR activation in steatotic AML-12 cells, which was confirmed by guggulsterones (FXR antagonist) or GW3965 (LXR agonist). Activation of FXR and LXR signaling caused by AA might increase AMPK-SIRT1 signaling and then contribute to modulating lipid accumulation and fatty acid synthesis, which suggested that activated FXR-LXR axis by AA represented an effective strategy for relieving NAFLD.


Assuntos
Diterpenos/farmacologia , Lipogênese/efeitos dos fármacos , Receptores X do Fígado/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Dieta Hiperlipídica , Diterpenos/química , Regulação da Expressão Gênica/efeitos dos fármacos , Receptores X do Fígado/agonistas , Receptores X do Fígado/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , PPAR alfa/genética , PPAR alfa/metabolismo , Ácido Palmítico/farmacologia , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/genética , Transdução de Sinais/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/sangue
2.
Nat Commun ; 10(1): 2987, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278260

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a fatal disease in which the intricate alveolar network of the lung is progressively replaced by fibrotic scars. Myofibroblasts are the effector cells that excessively deposit extracellular matrix proteins thus compromising lung structure and function. Emerging literature suggests a correlation between fibrosis and metabolic alterations in IPF. In this study, we show that the first-line antidiabetic drug metformin exerts potent antifibrotic effects in the lung by modulating metabolic pathways, inhibiting TGFß1 action, suppressing collagen formation, activating PPARγ signaling and inducing lipogenic differentiation in lung fibroblasts derived from IPF patients. Using genetic lineage tracing in a murine model of lung fibrosis, we show that metformin alters the fate of myofibroblasts and accelerates fibrosis resolution by inducing myofibroblast-to-lipofibroblast transdifferentiation. Detailed pathway analysis revealed a two-arm mechanism by which metformin accelerates fibrosis resolution. Our data report an antifibrotic role for metformin in the lung, thus warranting further therapeutic evaluation.


Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Lipogênese/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Metformina/farmacologia , Miofibroblastos/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Colágeno/biossíntese , Modelos Animais de Doenças , Humanos , Fibrose Pulmonar Idiopática/etiologia , Fibrose Pulmonar Idiopática/patologia , Pulmão/citologia , Pulmão/patologia , Masculino , Metformina/uso terapêutico , Camundongos , Miofibroblastos/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Cultura Primária de Células , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Resultado do Tratamento , Regulação para Cima/efeitos dos fármacos
3.
Life Sci ; 232: 116644, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31301418

RESUMO

AIMS: (5R)-5-hydroxytriptolide (LLDT-8) is a triptolide analog with excellent capability against cancers, cerebral ischemic injury and rheumatoid arthritis. Here, we discovered its hepatoprotective effects in a mouse model of non-alcoholic fatty liver disease (NAFLD) by ameliorating liver lipid accumulation. MAIN METHODS: Male C57BL/6J mice were fed with a high-fat/high-fructose (HFHFr) diet for 29 weeks to induce the pathological phenomena of NAFLD. Then the mice were treated with LLDT-8 (0.5mg/kg and 1mg/kg) or Vehicle for 8 weeks. Finally, the serum biochemical indexes, liver histological features, fatty acids (FAs) profile and related gene expression in liver were detected to investigate the effect of LLDT-8 on lipid accumulation and its possible mechanism. KEY FINDINGS: LLDT-8 treatment significantly inhibited hepatic injury featured by the decrease of serum alanine aminotransferase (ALT) and aspartate transaminase (AST), the lessening of hepatic ballooning and macrovesicular steatosis. Moreover, LLDT-8 could downregulate the expression of stearoyl-CoA desaturase 1 (SCD1), which further led to the lower ratios of C16:1/C16:0 and C18:1/C18:0 and thus inhibited lipid synthesis. LLDT-8 treatment also could upregulate liver peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyltransferase 1a (Cpt1a), peroxisomal acyl-CoA oxidase 1 (Acox1), long-chain acyl-CoA dehydrogenase (Acadl) and medium-chain acyl-CoA dehydrogenase (Acadm) expression levels involved in fatty acids oxidation (FAO) and markedly promoted lipolysis. SIGNIFICANCE: Our results provide a novel application of LLDT-8 in improving NAFLD.


Assuntos
Diterpenos/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Dieta Hiperlipídica , Modelos Animais de Doenças , Frutose/administração & dosagem , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/patologia , Oxirredução , PPAR alfa/metabolismo , Triglicerídeos/metabolismo
4.
Toxicol Lett ; 313: 1-10, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31170421

RESUMO

The constitutive androstane receptor(CAR) activation is connected with mitogenic effects leading to liver hyperplasia and tumorigenesis in rodents. CAR activators, including phenobarbital, are considered rodent non-genotoxic carcinogens. Recently, trans-3,4,5,4´-tetramethoxystilbene(TMS), a potential anticancer drug (DMU-212), have been shown to alleviate N-nitrosodiethylamine/phenobarbital-induced liver carcinogenesis. We studied whether TMS inhibits mouse Car to protect from the PB-induced tumorigenesis. Unexpectedly, we identified TMS as a murine CAR agonist in reporter gene experiments, in mouse hepatocytes, and in C57BL/6 mice in vivo. TMS up-regulated Car target genes Cyp2b10, Cyp2c29 and Cyp2c55 mRNAs, but down-regulated expression of genes involved in gluconeogenesis and lipogenesis. TMS did not change or down-regulate genes involved in liver proliferation or apoptosis such as Mki67, Foxm1, Myc, Mcl1, Pcna, Bcl2, or Mdm2, which were up-regulated by another Car ligand TCPOBOP. TMS did not increase liver weight and had no significant effect on Ki67 and Pcna labeling indices in mouse liver in vivo. In murine hepatic AML12 cells, we confirmed a Car-independent proapoptotic effect of TMS. We conclude that TMS is a Car ligand with limited effects on hepatocyte proliferation, likely due to promoting apoptosis in mouse hepatic cells, while controlling Car target genes involved in xenobiotic and endobiotic metabolism.


Assuntos
Anticarcinógenos/farmacologia , Proliferação de Células/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Neoplasias Hepáticas/prevenção & controle , Fígado/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/agonistas , Estilbenos/farmacologia , Animais , Anticarcinógenos/metabolismo , Apoptose/efeitos dos fármacos , Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Sítios de Ligação , Família 2 do Citocromo P450/genética , Família 2 do Citocromo P450/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Gluconeogênese/efeitos dos fármacos , Gluconeogênese/genética , Células Hep G2 , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Fígado/metabolismo , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Ligação Proteica , Piridinas/farmacologia , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Esteroide Hidroxilases/genética , Esteroide Hidroxilases/metabolismo , Estilbenos/metabolismo
5.
J Anim Sci ; 97(7): 3071-3088, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31063536

RESUMO

The objective of this study was to evaluate the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation to ewes during late gestation on finishing lamb liver and adipose tissue fatty acid (FA) profile and gene expression. Lambs born from ewes supplemented with Ca salts of EPA + DHA, or palm FA distillate (PFAD) high in palmitic and oleic acid at 0.39% DM during the last 50 d of gestation were used. Lambs were weaned at 61 d of age and adapted to a high concentrate diet for 1.5 mo. After adaptation, 74 lambs (28 pens) were blocked by sex and BW and used in a 2 × 2 factorial arrangement of treatments using the factors of dam supplementation (DS) and lamb supplementation (LS) of Ca salts of EPA + DHA or PFAD at 1.48% DM. Lambs were slaughtered after 42 d and liver and adipose tissue collected for FA and gene expression analysis. Liver concentrations of EPA and DHA were greater (P < 0.01) with LS of EPA + DHA vs. PFAD during the finishing period. In adipose tissue, a lamb × dam interaction was observed for EPA (P = 0.02) and DHA (P = 0.04); LS of EPA + DHA increased EPA and DHA, but the increase was greatest in lambs born from ewes supplemented with PFAD. No lamb × dam treatment interactions were observed for gene expression in liver tissue (P > 0.10). Hepatic mRNA abundance of hormone-sensitive lipase (HSL; P = 0.01) was greater in lambs born from EPA + DHA ewes vs. lambs from PFAD ewes. mRNA expression of stearoyl-CoA desaturase (P < 0.01), fatty acid synthase (P = 0.01), Δ5-desaturase (P < 0.01), and Δ6-desaturase (P < 0.01) were decreased in liver of EPA + DHA lambs. A significant lamb × dam diet interaction was observed for elongation of very long chain fatty acid 2 in adipose tissue (P = 0.01); lambs supplemented with the same FA as their dams had lower expression. Expression of HSL tended (P = 0.08) to be decreased in adipose of EPA + DHA lambs born from EPA + DHA ewes. The changes in mRNA expression suggest that lipogenesis decreased, and lipolysis increased in lamb liver with EPA + DHA vs. PFAD supplementation during the finishing period. In adipose tissue, changes suggest that lipogenesis decreased in lambs born from EPA + DHA supplemented dams and supplemented with EPA + DHA during the finishing period. In addition, these results suggest an interaction between supplementation of FA to dams during late gestation on lamb response of adipose tissue, but not liver, to FA supplementation during the finishing period.


Assuntos
Suplementos Nutricionais/análise , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Ácidos Graxos/farmacologia , Ovinos/fisiologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Ração Animal/análise , Animais , Cálcio/farmacologia , Dieta/veterinária , Ácido Eicosapentaenoico/análogos & derivados , Ácidos Graxos não Esterificados/metabolismo , Feminino , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Parto/efeitos dos fármacos , Gravidez , Distribuição Aleatória , Ovinos/genética , Desmame
6.
J Drugs Dermatol ; 18(5): 412-418, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31141847

RESUMO

Cortexolone 17α-propionate (clascoterone) is a novel topical androgen antagonist that is being analyzed for its ability to treat acne. The pathogenesis of acne is attributed to multiple factors, including altered sebum production, inflammatory processes, dysregulation of the hormone microenvironment, and the proliferation of the skin commensal bacteria, Propionibacterium acnes (P. acnes). Androgens induce the proliferation and differentiation of sebocytes, (cells that comprise the sebaceous gland), help regulate the synthesis of the lipids that are incorporated into sebum and stimulate the production of cytokines that are found in inflammatory acne lesions. Several studies have established that clascoterone is a potent antiandrogen that is well tolerated and has selective topical activity. Its potency as an acne therapeutic is currently being analyzed in a large phase 3 clinical trial. The study described herein elucidates for the first time the mechanism of action of clascoterone. Clascoterone was found to bind the androgen receptor (AR) with high affinity in vitro, inhibit AR-regulated transcription in a reporter cell line, and antagonize androgen-regulated lipid and inflammatory cytokine production in a dose-dependent manner in human primary sebocytes. In particular, when compared to another AR antagonist, spironolactone, clascoterone was significantly better at inhibiting inflammatory cytokine synthesis from sebocytes. Therefore, clascoterone may be an excellent candidate to be the first topical antiandrogen to treat acne. J Drugs Dermatol. 2019;18(5):412-418.


Assuntos
Acne Vulgar/tratamento farmacológico , Antagonistas de Receptores de Andrógenos/uso terapêutico , Cortodoxona/análogos & derivados , Propionatos/uso terapêutico , Glândulas Sebáceas/efeitos dos fármacos , Acne Vulgar/microbiologia , Antagonistas de Receptores de Andrógenos/farmacologia , Linhagem Celular/efeitos dos fármacos , Cortodoxona/farmacologia , Cortodoxona/uso terapêutico , Citocinas/metabolismo , Humanos , Lipogênese/efeitos dos fármacos , Propionatos/farmacologia , Propionibacterium acnes , Receptores Androgênicos/metabolismo , Glândulas Sebáceas/citologia , Glândulas Sebáceas/metabolismo
7.
Planta Med ; 85(9-10): 719-728, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31137047

RESUMO

Abnormal lipid metabolism, such as increased fatty acid uptake and esterification, is associated with nonalcoholic fatty liver disease (NAFLD). The aqueous extract of the aerial part of Angelica tenuissima Nakai (ATX) inhibited high-fat diet-induced hepatic steatosis in mice as well as oleic acid-induced neutral lipid accumulation in HepG2 cells. ATX decreased the mRNA and protein levels of CD36 and diglyceride acyltransferase 2 (DGAT2), the maturation of sterol regulatory element-binding proteins (SREBP), and the expression of the lipogenic target genes fasn and scd1. The ATX components, Z-ligustilide and n-butylidenephthalide, inhibited the expression of FATP5 and DGAT2 and thus oleic acid-induced lipid accumulation in HepG2 cells. These results suggest that ATX and its active components Z-ligustilide and n-butylidenephthalide inhibit fatty acid uptake and esterification in mice and have potential as therapeutics for NAFLD.


Assuntos
4-Butirolactona/análogos & derivados , Angelica/química , Metabolismo dos Lipídeos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Anidridos Ftálicos/farmacologia , 4-Butirolactona/isolamento & purificação , 4-Butirolactona/farmacologia , Animais , Dieta Hiperlipídica/efeitos adversos , Avaliação Pré-Clínica de Medicamentos/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Lipogênese/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ácido Oleico/farmacologia , Anidridos Ftálicos/isolamento & purificação , Componentes Aéreos da Planta/química , Extratos Vegetais/análise , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
8.
Molecules ; 24(9)2019 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-31083642

RESUMO

Lipogenesis plays a critical role in the growth and metastasis of tumors, which is becoming an attractive target for anti-tumor drugs. RA-XII, one of the cyclopeptide glycosides isolated from Rubia yunnanensis, exerts anti-tumor effects on liver cancer. However, the underlying mechanisms are not clear. In the present study, the effects of RA-XII on lipogenesis were evaluated and the underlying mechanisms were investigated. The results indicated that RA-XII strongly inhibited tumor growth and lipogenesis (triglycerides and lipid droplets) in HepG2 cells, and the expression of key factors involved in lipogenesis (SREBP, SCD, FASN) was also obviously downregulated. Further investigation showed that the anti-tumor effects of RA-XII were attenuated by SREBP knockdown. Moreover, RA-XII downregulated the expression of SREBP cleavage-activating protein (SCAP), an upstream regulator of SREBP, and siRNA of SCAP prevented its restrained effects on tumor growth and lipogenesis. In addition, the in vivo experiment showed that RA-XII strongly restrained the lipogenesis and growth of liver tumor in nude mice xenograft model. Taken together, these results indicate that RA-XII suppresses the liver cancer growth by inhibition of lipogenesis via SCAP-dependent SREBP suppression. The findings reveal the potentials of RA-XII to be used in a novel therapeutic approach for treating liver cancer.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipogênese/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Proteínas de Membrana/metabolismo , Peptídeos Cíclicos/uso terapêutico , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Células Hep G2 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Peptídeos Cíclicos/farmacologia
9.
BMC Complement Altern Med ; 19(1): 100, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068163

RESUMO

BACKGROUND: Obesity is a risk factor for many diseases including diabetes, cancer, arthritis, and cardiovascular diseases. Angiogenesis nourishes adipose tissues and contributes to obesity; it can be prevented by suppressing the expression of associated signaling molecules. Natural products have garnered attention owing to their safety and efficacy in treating several diseases, including obesity. METHODS: Crude Microcystins were extracted from the blooming Microcystis aeruginosa under stress conditions, by ultrasonication following by solvent extraction. The microcystin extract was evaluated for its potential of inhibiting angiogenesis and adipogenesis. The antiangiogenic activity of the microcystins extract was investigated using human umbilical vein endothelial cells (HUVECs), and its anti-obesity activity was determined in vitro by quantification of the accumulated lipids in mouse 3 T3-L1 cells via Oil Red O staining method. RESULTS: The microcystin extract suppressed HUVECs proliferation and tubes formation in Matrigel in a dose-dependent manner. RT-PCR analysis revealed the downregulation of the mRNA expression of angiogenesis-related signaling molecules, such as PI3K, ß-catenin, vascular endothelial growth factor receptor-2 (VEGFR-2), vascular endothelial-cadherin, Akt1, and NF-κB. Additionally, it inhibited the differentiation of premature 3 T3 cells and lipid accumulation in a dose-dependent manner. It suppressed adipogenesis and lipogenesis by reducing the expression level of peroxisome proliferator-activated receptor γ, CCAAT/enhancer binding protein α, and sterol regulatory element-binding protein. CONCLUSIONS: Crude microcystin exerts anti-angiogenic and anti-obesity effects due to the inhibitory effects on the genes expression of associated signaling molecules and transcriptional factors.


Assuntos
Adipogenia/efeitos dos fármacos , Inibidores da Angiogênese/farmacologia , Fármacos Antiobesidade/farmacologia , Microcistinas/farmacologia , Microcystis/química , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana , Humanos , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Camundongos , Neovascularização Patológica/metabolismo
10.
Int J Mol Sci ; 20(7)2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30987128

RESUMO

Obesity, a major risk factor for chronic diseases such as type 2 diabetes (T2D), represents a serious primary health problem worldwide. Dietary habits are of special interest to prevent and counteract the obesity and its associated metabolic disorders, including lipid steatosis. Capsaicin, a pungent compound of chili peppers, has been found to ameliorate diet-induced obesity in rodents and humans. The purpose of this study was to examine the effect of capsaicin on hepatic lipogenesis and to delineate the underlying signaling pathways involved, using HepG2 cells as an experimental model. Cellular neutral lipids, stained with BODIPY493/503, were quantified by flow cytometry, and the protein expression and activity were determined by immunoblotting. Capsaicin reduced basal neutral lipid content in HepG2 cells, as well that induced by troglitazone or by oleic acid. This effect of capsaicin was prevented by dorsomorphin and GW9662, pharmacological inhibitors of AMPK and PPARγ, respectively. In addition, capsaicin activated AMPK and inhibited the AKT/mTOR pathway, major regulators of hepatic lipogenesis. Furthermore, capsaicin blocked autophagy and increased PGC-1α protein. These results suggest that capsaicin behaves as an anti-lipogenic compound in HepG2 cells.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Capsaicina/farmacologia , Lipogênese/efeitos dos fármacos , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Autofagia/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Células Hep G2 , Humanos , Lipídeos/análise , Modelos Biológicos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Regulação para Cima/efeitos dos fármacos
11.
Nutrients ; 11(4)2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30991731

RESUMO

The omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) is implicated in theregulation of both lipid and carbohydrate metabolism. Thus, we questioned whether dietary DHAand low or high content of sucrose impact on metabolism in mice deficient for elongation of verylong-chain fatty acids 2 (ELOVL2), an enzyme involved in the endogenous DHA synthesis. Wefound that Elovl2 -/- mice fed a high-sucrose DHA-enriched diet followed by the high sucrose, highfat challenge significantly increased body weight. This diet affected the triglyceride rich lipoproteinfraction of plasma lipoproteins and changed the expression of several genes involved in lipidmetabolism in a white adipose tissue. Our findings suggest that lipogenesis in mammals issynergistically influenced by DHA dietary and sucrose content.


Assuntos
Tecido Adiposo Branco/efeitos dos fármacos , Sacarose na Dieta/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Lipogênese/efeitos dos fármacos , Ganho de Peso/efeitos dos fármacos , Acetiltransferases/genética , Acetiltransferases/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Dieta Hiperlipídica , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/sangue , Ácidos Docosa-Hexaenoicos/deficiência , Lipogênese/genética , Lipoproteínas/sangue , Camundongos Knockout , Triglicerídeos/sangue
12.
Gastroenterology ; 157(2): 552-568, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31029706

RESUMO

BACKGROUND & AIMS: Acetaminophen (APAP) overdose is a major cause of acute liver failure (ALF). Mitochondrial SH3BP5 (also called SAB) and phosphorylation of c-Jun N-terminal kinase (JNK) mediate the hepatotoxic effects of APAP. We investigated the involvement of steroidogenic acute regulatory protein (STARD1), a mitochondrial cholesterol transporter, in this process and sensitization by valproic acid (VPA), which depletes glutathione and stimulates steroidogenesis. METHODS: Nonfasted C57BL/6J mice (control) and mice with liver-specific deletion of STARD1 (Stard1ΔHep), SAB (SabΔHep), or JNK1 and JNK2 (Jnk1+2ΔHep) were given VPA with or without APAP. Liver tissues were collected and analyzed by histology and immunohistochemistry and for APAP metabolism, endoplasmic reticulum (ER) stress, and mitochondrial function. Adult human hepatocytes were transplanted into Fah-/-/Rag2-/-/Il2rg-/-/NOD (FRGN) mice to create mice with humanized livers. RESULTS: Administration of VPA before administration of APAP increased the severity of liver damage in control mice. The combination of VPA and APAP increased expression of CYP2E1, formation of NAPQI-protein adducts, and depletion of glutathione from liver tissues of control mice, resulting in ER stress and the upregulation of STARD1. Livers from control mice given VPA and APAP accumulated cholesterol in the mitochondria and had sustained mitochondrial depletion of glutathione and mitochondrial dysfunction. Inhibition of ER stress, by administration of tauroursodeoxycholic acid to control mice, prevented upregulation of STARD1 in liver and protected the mice from hepatoxicity following administration of VPA and APAP. Administration of N-acetylcysteine to control mice prevented VPA- and APAP-induced ER stress and liver injury. Stard1ΔHep mice were resistant to induction of ALF by VPA and APAP, despite increased mitochondrial levels of glutathione and phosphorylated JNK; we made similar observations in fasted Stard1ΔHep mice given APAP alone. SabΔHep mice or Jnk1+2ΔHep mice did not develop ALF following administration of VPA and APAP. The ability of VPA to increase the severity of APAP-induced liver damage was observed in FRGN mice with humanized liver. CONCLUSIONS: In studies of mice, we found that upregulation of STARD1 following ER stress mediates APAP hepatoxicity via SH3BP5 and phosphorylation of JNK1 and JNK2.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hepatócitos/patologia , Fosfoproteínas/metabolismo , Adulto , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Modelos Animais de Doenças , Overdose de Drogas/complicações , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/transplante , Humanos , Lipogênese/efeitos dos fármacos , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosfoproteínas/genética , Esteroides/metabolismo , Quimeras de Transplante , Regulação para Cima , Ácido Valproico/administração & dosagem
13.
Int J Mol Sci ; 20(8)2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31027178

RESUMO

Skin provides the first defense line against the environment while preserving physiological homeostasis. Subcutaneous tissues including fat depots that are important for maintaining skin structure and alleviating senescence are altered during aging. This study investigated whether theaflavin (TF) in green tea (GT) has skin rejuvenation effects. Specifically, we examined whether high ratio of TF contents can induce the subcutaneous adipogenesis supporting skin structure by modulating lipid metabolism. The co-fermented GT (CoF-GT) fraction containing a high level of TF was obtained by co-fermentation with garland chrysanthemum (Chrysanthemum coronarium) and the conventionally fermented GT (F-GT) fraction was also obtained. The effects of the CoF- or F-GT fractions on adipogenesis were assessed using primary human subcutaneous fat cells (hSCF). Adipogenesis was evaluated based on lipid droplet (LD) formation, as visualized by Oil Red O staining; by analyzing of adipogenesis-related factors by real-time quantitative polyperase chain reaction (RT-qPCR); and by measuring the concentration of adiponectin released into the culture medium by enzyme-linked immunosorbent assay. TF-enriched CoF-GT fraction did not adversely affect hSCF cell viability but induced their adipogenic differentiation, as evidenced by LD formation, upregulation of adipogenesis-related genes, and adiponectin secretion. TF and TF-enriched CoF-GT fraction promoted differentiation of hSCFs and can therefore be used as an ingredient in rejuvenating agents.


Assuntos
Adipócitos/citologia , Adipogenia/efeitos dos fármacos , Biflavonoides/farmacologia , Catequina/farmacologia , Gordura Subcutânea/citologia , Adipócitos/efeitos dos fármacos , Adipogenia/genética , Adiponectina/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Chrysanthemum/química , Fermentação/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Modelos Biológicos
14.
Nutrients ; 11(4)2019 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-30935037

RESUMO

The aim of this study was to investigate the effect of melatonin on hepatic lipid metabolism in hamsters with high-fat diet (HFD)-induced dyslipidemia. Male Syrian hamsters were kept on either a chow control (C) or HFD for four weeks. After four weeks, animals fed the HFD were further randomly assigned to four groups: high-fat only (P), melatonin low-dosage (L), medium-dosage (M), and high-dosage (H) groups. The L, M, and H groups, respectively, received 10, 20, and 50 mg/kg/day of a melatonin solution, while the P and C groups received the ethanol vehicle. After eight weeks of the intervention, results showed that a low dose of melatonin significantly reduced HFD-induced hepatic cholesterol and triglycerides; decreased plasma cholesterol, triglycerides, and low-density lipoprotein cholesterol; and increased plasma high-density lipoprotein cholesterol (p < 0.05). In addition, melatonin markedly decreased activities of the hepatic lipogenic enzymes, acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) (p < 0.05), and elevated the relative hepatic carnitine palmitoyltransferase-1α expression in hamsters with HFD-induced hyperlipidemia. Consequently, melatonin reduced activities of the hepatic lipogenic enzymes, ACC and FAS. In summary, chronic melatonin administration improved HFD-induced dyslipidemia and hepatic lipid accumulation in Syrian hamsters with HFD-induced dyslipidemia, which might have occurred through inhibiting the lipogenesis pathway.


Assuntos
Antioxidantes/farmacologia , Hiperlipidemias/tratamento farmacológico , Lipogênese/efeitos dos fármacos , Melatonina/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Acetil-CoA Carboxilase/metabolismo , Animais , Carnitina O-Palmitoiltransferase/metabolismo , Colesterol/metabolismo , LDL-Colesterol/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Ácido Graxo Sintases/metabolismo , Humanos , Hiperlipidemias/etiologia , Fígado/metabolismo , Masculino , Mesocricetus , Hepatopatia Gordurosa não Alcoólica/etiologia , Triglicerídeos/metabolismo
15.
Int J Mol Sci ; 20(7)2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30934807

RESUMO

Lipid accumulation in renal cells has been implicated in the pathogenesis of obesity-related kidney disease, and lipotoxicity in the kidney can be a surrogate marker for renal failure or renal fibrosis. Fatty acid oxidation provides energy to renal tubular cells. Ca2+ is required for mitochondrial ATP production and to decrease reactive oxygen species (ROS). However, how nifedipine (a calcium channel blocker) affects lipogenesis is unknown. We utilized rat NRK52E cells pre-treated with varying concentrations of nifedipine to examine the activity of lipogenesis enzymes and lipotoxicity. A positive control exposed to oleic acid was used for comparison. Nifedipine was found to activate acetyl Coenzyme A (CoA) synthetase, acetyl CoA carboxylase, long chain fatty acyl CoA elongase, ATP-citrate lyase, and 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase, suggesting elevated production of cholesterol and phospholipids. Nifedipine exposure induced a vast accumulation of cytosolic free fatty acids (FFA) and stimulated the production of reactive oxygen species, upregulated CD36 and KIM-1 (kidney injury molecule-1) expression, inhibited p-AMPK activity, and triggered the expression of SREBP-1/2 and lipin-1, underscoring the potential of nifedipine to induce lipotoxicity with renal damage. To our knowledge, this is the first report demonstrating nifedipine-induced lipid accumulation in the kidney.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Rim/metabolismo , Lipogênese/efeitos dos fármacos , Nifedipino/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Transcrição Genética/efeitos dos fármacos , Animais , Vias Biossintéticas/efeitos dos fármacos , Antígenos CD36/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Colesterol/metabolismo , Regulação para Baixo/efeitos dos fármacos , Espaço Intracelular/metabolismo , Rim/efeitos dos fármacos , Rim/enzimologia , Rim/lesões , Modelos Biológicos , PPAR alfa/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima/efeitos dos fármacos
16.
Mol Cell ; 74(1): 45-58.e7, 2019 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-30846317

RESUMO

Cells require a constant supply of fatty acids to survive and proliferate. Fatty acids incorporate into membrane and storage glycerolipids through a series of endoplasmic reticulum (ER) enzymes, but how these enzymes are regulated is not well understood. Here, using a combination of CRISPR-based genetic screens and unbiased lipidomics, we identified calcineurin B homologous protein 1 (CHP1) as a major regulator of ER glycerolipid synthesis. Loss of CHP1 severely reduces fatty acid incorporation and storage in mammalian cells and invertebrates. Mechanistically, CHP1 binds and activates GPAT4, which catalyzes the initial rate-limiting step in glycerolipid synthesis. GPAT4 activity requires CHP1 to be N-myristoylated, forming a key molecular interface between the two proteins. Interestingly, upon CHP1 loss, the peroxisomal enzyme, GNPAT, partially compensates for the loss of ER lipid synthesis, enabling cell proliferation. Thus, our work identifies a conserved regulator of glycerolipid metabolism and reveals plasticity in lipid synthesis of proliferating cells.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Retículo Endoplasmático/enzimologia , Glicerídeos/biossíntese , Glicerol-3-Fosfato O-Aciltransferase/metabolismo , Lipogênese , Células 3T3 , Aciltransferases/genética , Aciltransferases/metabolismo , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Ligação ao Cálcio/genética , Proliferação de Células , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/patologia , Ativação Enzimática , Regulação Enzimológica da Expressão Gênica , Glicerol-3-Fosfato O-Aciltransferase/genética , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , Células Jurkat , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Camundongos , Ácido Palmítico/toxicidade , Ligação Proteica
17.
Nutrients ; 11(3)2019 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-30832407

RESUMO

In this study, we aimed to determine the relative effectiveness of common dietary polyphenols or the isoquinoline alkaloid berberine in protecting against molecular mechanisms underlying non-alcoholic fatty liver disease (NAFLD) involving changes to cellular lipid metabolism and bioenergetics. In a model of steatosis using HepG2 hepatocytes, exposure of the cells to 1.5 mM oleic acid (OA) for 24 h caused steatosis and distorted cell morphology, induced the expression of mRNA for enzymes that are involved in lipogenesis and fatty acid oxidation (FAS and CPT1A), and impaired indices of aerobic energy metabolism (PPARγ mRNA expression, mitochondrial membrane potential (MMP), and galactose-supported ATP production). Co-treatment with 10 µM of selected polyphenols all strongly protected against the steatosis and changes in cell morphology. All polyphenols, except cyanidin, inhibited the effects on FAS and PPARγ and further increased CPT1A1 expression, suggesting a shift toward increased ß-oxidation. Resveratrol, quercetin, catechin, and cyanidin, however not kuromanin or berberine, ameliorated the decreases in MMP and galactose-derived ATP. Berberine was unique in worsening the decrease in galactose-derived ATP. In further investigations of the mechanisms involved, resveratrol, catechin, and berberine increased SIRT1 enzyme activity and p-AMPKαThr172 protein, which are involved in mitochondrial biogenesis. In conclusion, selected polyphenols all protected against steatosis with similar effectiveness, however through different mechanisms that increased aerobic lipid metabolism and mitochondrial function.


Assuntos
Fígado Gorduroso/metabolismo , Mitocôndrias Hepáticas/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Polifenóis/farmacologia , Substâncias Protetoras/farmacologia , Carnitina O-Palmitoiltransferase/efeitos dos fármacos , Fígado Gorduroso/induzido quimicamente , Células Hep G2/efeitos dos fármacos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Ácido Oleico , Oxirredução/efeitos dos fármacos
18.
J Sci Food Agric ; 99(8): 4158-4166, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30767223

RESUMO

BACKGROUND: Saponins have been shown to possess many pharmacological properties, including altered fat metabolism. The black sea cucumber, Holothuria leucospilota, is a marine animal that contains a specialized organ called a Cuvierian tubule that produces and secrete the bioactive saponins into the tubules and body wall. Therefore, the aims of this study are to investigate the anti-obesity effect of saponins extracted from body wall and Cuvierian tubules of H. leucospilota. RESULTS: The butanol extracts of H. leucospilota body wall and Cuvierian tubules containing high amounts of saponins significantly reduced fat deposition and triglyceride levels in Caenorhabditis elegans fed with 50 mmol L-1 glucose. Moreover, the saponin-enriched extracts of H. leucospilota significantly restored the lifespan of 2% glucose-fed worms (18.71%). Green fluorescence protein-labeled sbp-1 gene expression and nuclear translocation of daf-16 were also significantly decreased in H. leucospilota treatment. The saponin-enriched extracts downregulated the messenger RNA expressions of genes involved in fat storage and metabolism, including sbp-1, cebp, and daf-16 but upregulated the expression of nhr-49 gene. CONCLUSION: Our results suggest that H. leucospilota-derived saponins may mediate the reduction of glucose-induced fat accumulation through sbp-1, cebp, daf-16 and nhr-9 pathways. Therefore, the H. leucospilota extracts could be used as nutraceuticals for anti-obesity prevention. © 2019 Society of Chemical Industry.


Assuntos
Modelos Animais de Doenças , Gorduras/metabolismo , Holothuria/química , Lipogênese/efeitos dos fármacos , Obesidade/tratamento farmacológico , Saponinas/farmacologia , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Humanos , Obesidade/genética , Obesidade/metabolismo , Triglicerídeos/metabolismo
19.
PLoS One ; 14(2): e0210828, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30735525

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is one of the main causes of chronic liver disease. NAFLD begins with excessive lipid accumulation in the liver and progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is closely linked to dysregulated hepatic lipid metabolism. Although recent studies have reported that epidermal growth factor receptor (EGFR) signaling regulates lipid metabolism, the roles of EGFR and EGFR inhibitors as modulators of lipid metabolism are largely unknown. Here, we investigated whether inhibiting EGFR using the EGFR tyrosine kinase inhibitor (TKI) PD153035 improves NAFLD. Our results demonstrate that EGFR was activated in liver tissues from high fat diet (HFD)-induced NAFLD mice. Inhibiting EGFR using PD153035 significantly reduced phosphatidylinositol-3-kinase/protein kinase B signaling and sterol responsive elementary binding protein 1 and 2 expression, which prevented HFD-induced hepatic steatosis and hypercholesterolemia by reducing de novo lipogenesis and cholesterol synthesis and enhancing fatty acid oxidation. Additionally, inhibiting EGFR improved HFD-induced glucose intolerance. In conclusion, these results indicate that EGFR plays an important role in NAFLD and is a potential therapeutic target.


Assuntos
Diabetes Mellitus Experimental , Gorduras na Dieta/efeitos adversos , Receptores ErbB/antagonistas & inibidores , Hepatopatia Gordurosa não Alcoólica , Quinazolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/epidemiologia , Diabetes Mellitus Experimental/patologia , Gorduras na Dieta/farmacologia , Receptores ErbB/metabolismo , Humanos , Lipogênese/efeitos dos fármacos , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/patologia
20.
Nat Commun ; 10(1): 623, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30733434

RESUMO

Insulin-induced gene (Insig) negatively regulates SREBP-mediated de novo fatty acid synthesis in the liver. However, the upstream regulation of Insig is incompletely understood. Here we report that AMPK interacts with and mediates phosphorylation of Insig. Thr222 phosphorylation following AMPK activation is required for protein stabilization of Insig-1, inhibition of cleavage and processing of SREBP-1, and lipogenic gene expression in response to metformin or A769662. AMPK-dependent phosphorylation ablates Insig's interaction with E3 ubiquitin ligase gp78 and represses its ubiquitination and degradation, whereas AMPK deficiency shows opposite effects. Interestingly, activation of AMPK by metformin causes an augmentation of Insig stability and reduction of lipogenic gene expression, and leads to the attenuation of hepatic steatosis in HFHS diet-fed mice. Moreover, hepatic overexpression of Insig-1 rescues hepatic steatosis in liver-specific AMPKα2 knockout mice fed with HFHS diet. These findings uncover a novel effector of AMPK. Targeting Insig may have the therapeutic potential for treating fatty liver disease and related disorders.


Assuntos
Regulação da Expressão Gênica , Lipogênese/genética , Animais , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipogênese/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Metformina/farmacologia , Camundongos , Camundongos Knockout , Fosforilação/efeitos dos fármacos , Pironas/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Tiofenos/farmacologia , Ubiquitinação/efeitos dos fármacos
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