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1.
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
2.
Am J Physiol Regul Integr Comp Physiol ; 318(2): R453-R467, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31913683

RESUMO

Induced by overfeeding, hepatic steatosis is a process exploited for the "foie gras" production in mule ducks. To better understand the mechanisms underlying its development, the physiological responses of mule ducks overfed with corn for a duration of 11 days were analyzed. A kinetic analysis of glucose and lipid metabolism and cell protection mechanisms was performed on 96 male mule ducks during overfeeding with three sampling times (after the 4th, the 12th, and the 22nd meal). Gene expression and protein analysis realized on the liver, muscle, and abdominal fat showed an activation of a cholesterol biosynthetic pathway during the complete overfeeding period mainly in livers with significant correlations between its weight and its cholesterolemia (r = 0.88; P < 0.0001) and between the liver weight and the hmgcr and soat1 expression (r = 0.4, P < 0.0001 and r = 0.67; P < 0.0001, respectively). Results also revealed an activation of insulin and amino acid cells signaling a pathway suggesting that ducks boost insulin sensitivity to raise glucose uptake and use via glycolysis and lipogenesis. Cellular stress analysis revealed an upregulation of key autophagy-related gene expression atg8 and sqstm1(P < 0.0001) during the complete overfeeding period, mainly in the liver, in contrast to an induction of cyp2e1(P < 0.0001), suggesting that autophagy could be suppressed during steatosis development. This study has highlighted different mechanisms enabling mule ducks to efficiently handle the starch overload by keeping its liver in a nonpathological state. Moreover, it has revealed potential biomarker candidates of hepatic steatosis as plasma cholesterol for the liver weight.


Assuntos
Glicemia/metabolismo , Patos/metabolismo , Ingestão de Energia , Metabolismo Energético , Fígado Gorduroso/metabolismo , Lipogênese , Fígado/metabolismo , Estresse Fisiológico , Ração Animal , Fenômenos Fisiológicos da Nutrição Animal , Animais , Glicemia/genética , Metabolismo Energético/genética , Fígado Gorduroso/etiologia , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Regulação Enzimológica da Expressão Gênica , Cinética , Lipogênese/genética , Fígado/patologia , Masculino , Estado Nutricional , Tamanho do Órgão
3.
Nat Commun ; 11(1): 575, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996678

RESUMO

mTORC2 phosphorylates AKT in a hydrophobic motif site that is a biomarker of insulin sensitivity. In brown adipocytes, mTORC2 regulates glucose and lipid metabolism, however the mechanism has been unclear because downstream AKT signaling appears unaffected by mTORC2 loss. Here, by applying immunoblotting, targeted phosphoproteomics and metabolite profiling, we identify ATP-citrate lyase (ACLY) as a distinctly mTORC2-sensitive AKT substrate in brown preadipocytes. mTORC2 appears dispensable for most other AKT actions examined, indicating a previously unappreciated selectivity in mTORC2-AKT signaling. Rescue experiments suggest brown preadipocytes require the mTORC2/AKT/ACLY pathway to induce PPAR-gamma and establish the epigenetic landscape during differentiation. Evidence in mature brown adipocytes also suggests mTORC2 acts through ACLY to increase carbohydrate response element binding protein (ChREBP) activity, histone acetylation, and gluco-lipogenic gene expression. Substrate utilization studies additionally implicate mTORC2 in promoting acetyl-CoA synthesis from acetate through acetyl-CoA synthetase 2 (ACSS2). These data suggest that a principal mTORC2 action is controlling nuclear-cytoplasmic acetyl-CoA synthesis.


Assuntos
ATP Citrato (pro-S)-Liase/metabolismo , Adipócitos Marrons/metabolismo , Lipogênese/fisiologia , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Acetato-CoA Ligase/metabolismo , Animais , Proteínas de Transporte , Epigênese Genética , Ácido Graxo Sintases , Edição de Genes , Expressão Gênica , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Células HEK293 , Histonas/metabolismo , Humanos , Lipogênese/genética , Camundongos , Camundongos Endogâmicos C57BL , PPAR gama/metabolismo , Fosforilação , Proteômica , Elementos de Resposta
4.
J Dairy Sci ; 103(1): 340-351, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31733862

RESUMO

The synthesis of milk components in bovine mammary epithelial cells (BMEC) requires an adequate supply of energy. The AMP-activated protein kinase (AMPK) is a cellular energy gauge that controls anabolic and catabolic processes to maintain a balance between energy supply and demand. The objectives of this study were to assess the role of AMPK on de novo lipid and lactose synthesis, as well as its regulation by glucose and acetate availability in BMEC. We isolated primary BMEC from the mammary tissue of 3 lactating Holstein cows and differentiated them with lactogenic hormones for 4 d. We measured protein abundance, site-specific phosphorylation, and proteolytic processing by immunoblotting. We quantified the expression of genes involved in lipid and lactose synthesis using real-time quantitative PCR. We measured de novo lipid and lactose synthesis by incorporation of radioactive substrates. We analyzed data by ANOVA using a randomized complete block design with PROC MIXED in SAS. To assess the effect of AMPK activation on milk component synthesis, we treated BMEC with 100 µM A-769662 (A76; an allosteric activator of AMPK) or vehicle control for 16 h. Consistent with activation of AMPK, A76 increased phosphorylation of its downstream targets ACC Ser79 and TSC2 Ser1387 by 144% and 26%, respectively. Activation of AMPK decreased lipid synthesis by 19%. This effect was accompanied by increased expression of FABP3. Activation of AMPK reduced the proportion of mature SREBP-1c. In addition, AMPK activation reduced lactose synthesis by 24% and lowered the expression of SLC2A1, the gene encoding GLUT1. To assess the regulation of AMPK by energy substrate availability, we incubated BMEC in a control medium containing 4 mM D-glucose and 1 mM sodium acetate, or medium lacking glucose or acetate, for 4 h. Compared with the control medium, deprivation of glucose or acetate promoted AMPKα phosphorylation at Thr172 by 84% or 58%, respectively. Activation of AMPK was significantly increased in BMEC only when the medium was devoid of glucose for at least 4 h. We concluded that activation of AMPK inhibits de novo lipid and lactose synthesis in BMEC. Further studies are needed to assess the physiological relevance of AMPK activation for milk composition in vivo and to identify the mechanisms mediating its effects on milk component synthesis.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Células Epiteliais/metabolismo , Lactose/biossíntese , Lipídeos/biossíntese , Glândulas Mamárias Animais/citologia , Proteínas Quinases Ativadas por AMP/genética , Animais , Metabolismo dos Carboidratos , Bovinos , Contagem de Células , Células Epiteliais/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Lactação , Lipogênese/genética , Leite/química , Leite/metabolismo , Fosforilação/efeitos dos fármacos , Pironas/farmacologia , Tiofenos/farmacologia
5.
Metabolism ; 102: 154000, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31678070

RESUMO

OBJECTIVE: Supplementation with serine attenuates alcoholic fatty liver by regulating homocysteine metabolism and lipogenesis. However, little is known about serine metabolism in fatty liver disease (FLD). We aimed to investigate the changes in serine biosynthetic pathways in humans and animal models of fatty liver and their contribution to the development of FLD. METHODS: High-fat diet (HFD)-induced steatosis and methionine-choline-deficient diet-induced steatohepatitis animal models were employed. Human serum samples were obtained from patients with FLD whose proton density fat fraction was estimated by magnetic resonance imaging. 3-Phosphoglycerate dehydrogenase (Phgdh)-knockout mouse embryonic fibroblasts (MEF) and transgenic mice overexpressing Phgdh (Tg-phgdh) were used to evaluate the role of serine metabolism in the development of FLD. RESULTS: Expression of Phgdh was markedly reduced in the animal models. There were significant negative correlations of the serum serine with the liver fat fraction, serum alanine transaminase, and triglyceride levels among patients with FLD. Increased lipid accumulation and reduced NAD+ and SIRT1 activity were observed in Phgdh-knockout MEF and primary hepatocytes incubated with free fatty acids; these effects were reversed by overexpression of Phgdh. Tg-Phgdh mice showed significantly reduced hepatic triglyceride accumulation compared with wild-type littermates fed a HFD, which was accompanied by increased SIRT1 activity and reduced expression of lipogenic genes and proteins. CONCLUSIONS: Human and experimental data suggest that reduced Phgdh expression and serine levels are closely associated with the development of FLD.


Assuntos
Gliceraldeído-3-Fosfato Desidrogenases/genética , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Serina/metabolismo , Animais , Células Cultivadas , Estudos de Coortes , Dieta Hiperlipídica , Regulação para Baixo , Embrião de Mamíferos , Feminino , Regulação Enzimológica da Expressão Gênica , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Humanos , Metabolismo dos Lipídeos/genética , Lipogênese/genética , Fígado/química , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/patologia , Serina/análise
6.
Meat Sci ; 160: 107962, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31683256

RESUMO

Two studies were carried out, the first with the objective to evaluate performance, beef quality and expression of genes involved in lipid metabolism in the muscle of bulls fed with or without low-fat dried distillers grains with solubles (DDGS, 21% DM) in the diet. In the second, eight rumen-fistulated bulls were assigned in a switch back design to evaluate the fatty acid profile of omasal fluid. We hypothesized that bulls fed DDGS may have an improved fatty acid profile and expression of genes involved in lipid metabolism may be altered, without affecting performance. Bulls fed DDGS had greater (P < .05) concentrations of PUFA n-6 in the omasum and muscle. CLA t10, c12 content was higher and there was lower expression of the LPL gene (P = .05) in the muscle of animals fed DDGS (P = .03). In conclusion, DDGS can be used as a protein feedstuff because it maintains beef quality.


Assuntos
Bovinos/fisiologia , Dieta/veterinária , Carne Vermelha/análise , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Grão Comestível , Ácidos Graxos/metabolismo , Expressão Gênica , Lipogênese/genética , Masculino , Omaso/química
7.
Int J Mol Sci ; 20(24)2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31842467

RESUMO

The interaction of leptin with its hepatic longest receptor (OBRb) promotes the phosphorylation of signal transducer and activator of transcription-3 (STAT3), protecting the liver from lipid accumulation. However, leptin signalling is disrupted in hepatic steatosis, causing leptin resistance. One promising strategy to combat this problem is the use of bioactive compounds such as polyphenols. Since resveratrol (RSV) is a modulator of lipid homeostasis in the liver, we investigated whether treatment with different doses of RSV restores appropriate leptin action and fat accumulation in palmitate-induced steatotic human hepatoma (HepG2) cells. Both RSV metabolism and the expression of molecules implicated in leptin signalling were analysed. RSV at a 10 µM concentration was entirely metabolized to resveratrol-3-sulfate after 24 and counteracted leptin resistance by increasing the protein levels of OBRb. In addition, RSV downregulated the expression of lipogenic genes including fatty acid synthase (Fas) and stearoyl-CoA desaturase-1 (Scd1) without any significant change in Sirtuin-1 (SIRT1) enzymatic activity. These results demonstrate that RSV restored leptin sensitivity in a cellular model of hepatic steatosis in a SIRT1-independent manner.


Assuntos
Leptina/metabolismo , Palmitatos/metabolismo , Receptores para Leptina/metabolismo , Resveratrol/farmacologia , Biomarcadores , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Oxirredução/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo
8.
Int J Mol Sci ; 20(19)2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31569635

RESUMO

Poria cocos Wolf (PCW) is an edible, pharmaceutical mushroom with remarkable biological properties including anti-tumor, anti-inflammation, anti-oxidation, anti-ageing, and anti-diabetic effects. In the current study, we investigated the effects of PCW extract on hepatic steatosis under in vitro and in vivo conditions, and elucidated the underlying mechanisms. In this study, a mixture of HepG2 cells treated with free fatty acid (FFA)-palmitic and oleic acid-and high-fat diet (HFD)-fed obese mice were used; in this background, the triglyceride (TG) levels in HepG2 cells and mice liver were measured, and the expression levels of genes associated with lipogenesis, fatty acid oxidation, endoplasmic reticulum (ER) stress, and autophagy were determined. Treatment of HepG2 cells with FFA enhanced intracellular TG levels in HepG2 cells, but co-treatment with PCW significantly attenuated the TG levels. Notably, PCW significantly enhanced the phosphorylation of AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), and sterol regulatory element-binding protein-1c (SREBP-1c) in FFA-treated HepG2 cells. PCW downregulated the expression of lipogenesis-related genes, but upregulated the expression of genes associated with fatty acid oxidation. Further, PCW inhibited FFA-induced expression of ER stress markers and induced autophagy proteins. However, inhibition of AMPK significantly attenuated the beneficial effects of PCW in HepG2 cells. Moreover, PCW efficiently decreased HFD-induced hepatic TG accumulation in vivo and increased the phosphorylation of hepatic AMPK. Three compounds present in PCW including poricoic acid, pachymic acid, and ergosterol, significantly decreased FFA-induced increase in intracellular TG levels, consistent with increased AMPK phosphorylation, suggesting that poricoic acid, pachymic acid, and ergosterol are responsible for PCW-mediated amelioration of hepatic steatosis. Taken together, these results demonstrated that PCW ameliorates hepatic steatosis through the regulation of lipid metabolism, inhibition of ER stress, and activation of autophagy in an AMPK-dependent manner. This suggested that PCW can be potentially used for the treatment of hepatic steatosis.


Assuntos
Agaricales/química , Autofagia/efeitos dos fármacos , Extratos Celulares/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Poria/química , Animais , Extratos Celulares/química , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Ácidos Graxos/metabolismo , Ácidos Graxos/farmacologia , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Masculino , Camundongos , Inibidores de Proteínas Quinases/farmacologia
9.
Mol Cell ; 76(5): 811-825.e14, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31628041

RESUMO

Physical contact between organelles is vital to the function of eukaryotic cells. Lipid droplets (LDs) are dynamic organelles specialized in lipid storage that interact physically with mitochondria in several cell types. The mechanisms coupling these organelles are, however, poorly understood, and the cell-biological function of their interaction remains largely unknown. Here, we discover in adipocytes that the outer mitochondrial membrane protein MIGA2 links mitochondria to LDs. We identify an amphipathic LD-targeting motif and reveal that MIGA2 binds to the membrane proteins VAP-A or VAP-B in the endoplasmic reticulum (ER). We find that in adipocytes MIGA2 is involved in promoting triglyceride (TAG) synthesis from non-lipid precursors. Our data indicate that MIGA2 links reactions of de novo lipogenesis in mitochondria to TAG production in the ER, thereby facilitating efficient lipid storage in LDs. Based on its presence in many tissues, MIGA2 is likely critical for lipid and energy homeostasis in a wide spectrum of cell types.


Assuntos
Adipócitos/metabolismo , Lipogênese/fisiologia , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/metabolismo , Células 3T3 , Adipócitos/fisiologia , Animais , Células COS , Diferenciação Celular/fisiologia , Retículo Endoplasmático/metabolismo , Células HEK293 , Humanos , Gotículas Lipídicas/metabolismo , Lipogênese/genética , Proteínas de Membrana/fisiologia , Camundongos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/fisiologia , Triglicerídeos/biossíntese , Proteínas de Transporte Vesicular/metabolismo
10.
Lipids Health Dis ; 18(1): 168, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477154

RESUMO

BACKGROUND: The alteration of lipid metabolism in cancer cells is recognized as one of the most important metabolic hallmarks of cancer. Membrane rafts defined as plasma membrane microdomains enriched in cholesterol and sphingolipids serve as platforms for signaling regulation in cancer. The main purpose of this study was to evaluate the effect of the cholesterol metabolite, 4-cholesten-3-one, on lipid metabolism and membrane raft integrity in two breast cancer cell lines, MCF-7 and MDA-MB-231. Its ability to reduce cell viability and migration has also been investigated. METHODS: RT-qPCR was performed to evaluate the expression of enzymes involved in lipogenesis and cholesterol synthesis, and ABCG1 and ABCA1 transporters involved in cholesterol efflux. Its effect on cell viability and migration was studied using the MTT assay, the wound healing assay and the Transwell migration assay, respectively. The effect of 4-cholesten-3-one on membrane rafts integrity was investigated by studying the protein expression of flotillin-2, a membrane raft marker, and raft-enriched EGFR by western blot. RESULTS: Interestingly, we found that 4-cholesten-3-one treatment decreased mRNA expression of different enzymes including ACC1, FASN, SCD1 and HMGCR. We further demonstrated that 4-cholesten-3-one increased the expression of ABCG1 and ABCA1. We also found that 4-cholesten-3-one decreased the viability of MCF-7 and MDA-MB-231 cells. This effect was neutralized after treatment with LXR inverse agonist or after LXRß knockdown by siRNA. As a result, we also demonstrated that 4-cholesten-3-one disrupts membrane rafts and cell migration capacity. CONCLUSION: Our results show that 4-cholesten-3-one exerts promising antitumor activity by altering LXR-dependent lipid metabolism in breast cancer cells without increasing lipogenesis.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Colestenonas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Receptores X do Fígado/genética , Microdomínios da Membrana/efeitos dos fármacos , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Ácido Graxo Sintase Tipo I/genética , Ácido Graxo Sintase Tipo I/metabolismo , Humanos , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Lipogênese/genética , Receptores X do Fígado/metabolismo , Células MCF-7 , Microdomínios da Membrana/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Transdução de Sinais , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Células THP-1
11.
Nutrients ; 11(9)2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31514294

RESUMO

Prunus persica (L.) Batsch is a deciduous fruit tree cultivated worldwide. The flower of P. persica (PPF), commonly called the peach blossom, is currently consumed as a tea for weight loss in East Asia; however, its anti-obesity effects have yet to be demonstrated in vitro or in vivo. Since PPF is rich in phytochemicals with anti-obesity properties, we aimed to investigate the effects of PPF on obesity and its underlying mechanism using a diet-induced obesity model. Male C57BL/6 mice were fed either normal diet, high-fat diet (HFD), or HFD containing 0.2% or 0.6% PPF water extract for 8 weeks. PPF significantly reduced body weight, abdominal fat mass, serum glucose, alanine transaminase and aspartate aminotransferase levels, and liver and spleen weights compared to the HFD control group. Real-time quantitative polymerase chain reaction analysis revealed that PPF suppressed lipogenic gene expression, including stearoyl-CoA desaturase-1 and -2 and fatty acid synthase, and up-regulated the fatty acid ß-oxidation gene, carnitine palmitoyltransferase-1, in the liver. Our results suggest that PPF exerts anti-obesity effects in obese mice and these beneficial effects might be mediated through improved hepatic lipid metabolism by reducing lipogenesis and increasing fatty acid oxidation.


Assuntos
Fármacos Antiobesidade/farmacologia , Ácidos Graxos/metabolismo , Flores/química , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Obesidade/prevenção & controle , Extratos Vegetais/farmacologia , Prunus persica/química , Perda de Peso/efeitos dos fármacos , Animais , Fármacos Antiobesidade/isolamento & purificação , Biomarcadores/sangue , Dieta Hiperlipídica , Modelos Animais de Doenças , Ingestão de Alimentos , Regulação da Expressão Gênica , Lipogênese/genética , Fígado/enzimologia , Masculino , Camundongos Endogâmicos C57BL , Obesidade/sangue , Obesidade/genética , Obesidade/fisiopatologia , Tamanho do Órgão , Oxirredução , Extratos Vegetais/isolamento & purificação
12.
Nutrients ; 11(8)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374969

RESUMO

A high-calorie diet causes fat accumulation and oxidative stress in the liver, leading to fatty liver and eventually non-alcoholic steatohepatitis (NASH). Melon GliSODin® is used as a nutritional supplement because of its antioxidant activity. This study aimed to assess the antioxidant activity of Melon GliSODin® and its effectiveness in preventing NASH, which primarily results from oxidative stress. Furthermore, we verified the protective effect of Melon GliSODin® by administering it to a mouse model of diet-induced NASH. Melon GliSODin® suppressed liver fibrosis and fat accumulation, which is characteristic of the NASH phenotype. Gene expression analysis confirmed the suppression of fat synthesis and activation of antioxidative mechanisms. These results show that Melon GliSODin® mitigates NASH onset at the molecular level, suggesting its potential application as a NASH preventive agent.


Assuntos
Antioxidantes/farmacologia , Cucurbitaceae/química , Lipogênese/efeitos dos fármacos , Cirrose Hepática Experimental/prevenção & controle , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Antioxidantes/isolamento & purificação , Dieta Hiperlipídica , Regulação para Baixo , Regulação da Expressão Gênica , Lipogênese/genética , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Extratos Vegetais/isolamento & purificação
13.
G3 (Bethesda) ; 9(7): 2161-2170, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31289120

RESUMO

Increasing evidence indicates that parental diet affects the metabolism and health of offspring. It is reported that paternal low-protein diet (pLPD) induces glucose intolerance and the expression of genes involved in cholesterol biosynthesis in mouse offspring liver. The aim of the present study was to determine the effect of a pLPD on gene expression in offspring white adipose tissue (WAT), another important tissue for the regulation of metabolism. RNA-seq analysis indicated that pLPD up- and down-regulated 54 and 274 genes, respectively, in offspring WAT. The mRNA expression of many genes involved in lipogenesis was down-regulated by pLPD feeding, which may contribute to metabolic disorder. The expression of carbohydrate response element-binding protein ß (ChREBP-ß), an important lipogenic transcription factor, was also significantly lower in the WAT of pLPD offspring, which may have mediated the down-regulation of the lipogenic genes. By contrast, the LPD did not affect the expression of lipogenic genes in the WAT of the male progenitor, but increased the expression of lipid oxidation genes, suggesting that a LPD may reduce lipogenesis using different mechanisms in parents and offspring. These findings add to our understanding of how paternal diet can regulate metabolism in their offspring.


Assuntos
Adipócitos/metabolismo , Dieta com Restrição de Proteínas , Herança Paterna , Transcriptoma , Animais , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Lipogênese/genética , Camundongos , Modelos Biológicos
14.
Biomed Res Int ; 2019: 1969413, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31312653

RESUMO

The positive regulatory domain containing 16 (PRDM16) gene is a dominant transcriptional regulator that favors the "browning" of white adipocytes in rodents. Since the "browning" of white fat is important in pig in terms of producing heat fighting against cold environment, avoiding obesity, and improving meat quality, understanding the critical role that PRDM16 gene played in pig adipose "browning" and energy metabolism is of great significance. However, the constitution of pig fat differs a lot from rodents and human as they do not have brown adipose tissue (BAT) even in the newborn piglets. In this study, we isolated porcine primary preadipocytes and investigated the function of PRDM16 during preadipocytes differentiation. Our results showed that overexpression of the PR domain of PRDM16 repressed the differentiation of porcine preadipocytes, indicated by oil red O staining and the deposition of the triglyceride. Overexpression of the PR domain significantly increased the level of lipolysis and mitochondrial oxidative capacity detected by Western blotting during differentiation. Furthermore, we purified the protein coded by the PR domain and demonstrated that this protein has the H3K9me1 methyltransferase activity. In conclusion, the PR domain of the porcine PRDM16 gene repressed the mature of the porcine preadipocytes by promoting its oxidative activity.


Assuntos
Tecido Adiposo Branco/crescimento & desenvolvimento , Metabolismo Energético/genética , Lipogênese/genética , Obesidade/genética , Adipócitos/metabolismo , Tecido Adiposo Marrom/crescimento & desenvolvimento , Tecido Adiposo Branco/metabolismo , Animais , Diferenciação Celular/genética , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica , Humanos , Lipólise/genética , Obesidade/fisiopatologia , Suínos , Termogênese/genética , Fatores de Transcrição/genética , Dedos de Zinco/genética
15.
Biomed Pharmacother ; 118: 109130, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31306969

RESUMO

OBJECTIVES: The objective of this work was to determine the specific mechanisms by which resveratrol inhibits lipogenesis and stimulates lipolysis. METHODS: Twelve male mice were individually introduced into a metabolic cage for 24 h to measure basal metabolic rate, prior to intervention. They were randomly divided into two groups, resveratrol (RSV) and control (C), and administered resveratrol intraperitoneally or vehicle, respectively, for two consecutive days. After 24 h, the metabolic energy expenditure was again determined for 24 h, before mice were sacrificed. Protein and gene expression of different enzymes related to metabolism in the hepatic tissue, adipose tissue and gastrocnemius of mice were analyzed by RT-PCR, western blot or ELISA. RESULTS: We report that resveratrol lowers the respiratory quotient in old mice and that this may be due to the activation of fatty acid mobilization from white adipose tissue (because hormone-activated lipase expression is increased) and fatty acid transport into mitochondria and eventual oxidation in muscle and liver (because transport enzymes and beta oxidation enzymes are also increased). Indeed, we have observed that resveratrol in vivo causes an increase in the expression and phosphorylation of AMPKα in liver, muscle and adipose tissue and an increase in the expression of acyl-CoA synthetase, of carnitine palmitoyl transferase 1 and of carnitine acylcarnitine translocase, all enzymes involved in lipid catabolism. On the other hand, the levels of acetyl-CoA carboxylase as well as those its product, i.e. malonyl CoA, are decreased. CONCLUSIONS: We conclude that a controlled dose of resveratrol activates fatty acid mobilization and degradation and inhibits fatty acid synthesis in old mice. This is the first time that these effects of resveratrol in lipid metabolism in healthy old (non-obese) animals are reported.


Assuntos
Envelhecimento/metabolismo , Metabolismo Energético/efeitos dos fármacos , Ácidos Graxos/metabolismo , Lipogênese/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Resveratrol/farmacologia , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Envelhecimento/genética , Animais , Carnitina Aciltransferases/genética , Carnitina Aciltransferases/metabolismo , Metabolismo Energético/genética , Lipogênese/genética , Lipólise/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxirredução
16.
Nutrients ; 11(7)2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31277481

RESUMO

Allomyrina dichotoma larva is a nutritional-worthy future food resource and it contributes to multiple pharmacological functions. However, its antidiabetic effect and molecular mechanisms are not yet fully understood. Therefore, we investigated the hypolipidemic effect of A. dichotoma larva extract (ADLE) in a high-fat diet (HFD)-induced C57BL/6J mice model. Glucose tolerance and insulin sensitivity in HFD-induced diabetic mice significantly improved after ADLE administration for six weeks. The levels of serum triglyceride (TG), aspartate aminotransferase (AST), alanine transferase (ALT) activity, and lipid accumulation were increased in the liver of HFD-fed mice, but the levels were significantly reduced by the ADLE treatment. Moreover, hepatic fibrosis and inflammatory gene expression in the liver from HFD-treated mice were ameliorated by the ADLE treatment. Dephosphorylation of AMP-activated protein kinase (AMPK) by palmitate was inhibited in the ADLE treated HepG2 cells, and subsequently reduced expression of lipogenic genes, such as SREPBP-1c, ACC, and FAS were observed. The reduced expression of lipogenic genes and an increased phosphorylation of AMPK was also observed in the liver from diabetic mice treated with ADLE. In conclusion, ADLE ameliorates hyperlipidemia through inhibition of hepatic lipogenesis via activating the AMPK signaling pathway. These findings suggest that ADLE and its constituent bioactive compounds are valuable to prevent or treat hepatic insulin resistance in type 2 diabetes.


Assuntos
Besouros , Diabetes Mellitus/prevenção & controle , Dieta Hiperlipídica , Hipoglicemiantes/farmacologia , Resistência à Insulina , Fígado/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Besouros/química , Besouros/crescimento & desenvolvimento , Diabetes Mellitus/sangue , Diabetes Mellitus/enzimologia , Diabetes Mellitus/genética , Modelos Animais de Doenças , Regulação Enzimológica da Expressão Gênica , Células Hep G2 , Humanos , Hipoglicemiantes/isolamento & purificação , Larva/química , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Fígado/enzimologia , Masculino , Camundongos Endogâmicos C57BL , Fosforilação , Transdução de Sinais
17.
Ecotoxicol Environ Saf ; 181: 353-361, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31207574

RESUMO

Fatty liver is widely observed during Takifugu fasciatus production, but the mechanisms underlying fatty liver formation remain unknown. The present study was conducted to determine the potential effects of copper (Cu) on hepatic lipid deposition and metabolism in T. fasciatus after 21 days of exposure to Cu (levels: 0, 20 and 100 µg/L). Copper exposure decreased the weight gain rate (WG) in T. fasciatus, but increased the values of the viscerosomatic index (VSI) and hepatosomatic index (HSI) compared with the control. The time-dependent Cu accumulation in tissues increased as the Cu concentration increased. The order of Cu accumulation was liver > intestine > muscle. The lipid content, triglyceride (TG) content and lipoprotein lipase (LPL) activity increased after Cu exposure compared with the control. In addition, more lipid droplets and greater vacuolization were observed in the liver after exposure to 20 µg/L Cu than after 100 µg/L Cu. The expression of genes involved in lipogenesis (g6pd, 6pgd, lpl, fas and acc), lipolysis (hsl and cpt 1) and transcription (ppar α and ppar ©) was dependent on Cu. An analysis of the intestinal microbiome community showed that the highest values of the Chao 1 index, ACE, Shannon index and Simpson index were obtained in fish exposed to 20 µg/L Cu, whereas the lowest values were obtained after the 100 µg/L Cu treatment. The Principal Coordinates Analysis (PCoA) plots of the data revealed structural differences in the groups treated with Cu compared with the control group. At the phylum level, the intestinal microbiota in the Cu-treated and control fish were dominated by Proteobacteria and Bacteroidetes. The higher Firmicutes to Bacteroidetes ratio was observed in fish treated with 20 µg/L Cu compared with other groups, while the lowest ratio was observed in fish exposed to 100 µg/L Cu. Our study revealed the mechanisms by which Cu exposure altered (i) lipid deposition in the body and (ii) the intestinal microbiome, which may contribute to maintain the health status of T. fasciatus for the aquaculture.


Assuntos
Cobre/toxicidade , Fígado Gorduroso/veterinária , Doenças dos Peixes/induzido quimicamente , Takifugu , Poluentes Químicos da Água/toxicidade , Animais , Cobre/farmacocinética , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/metabolismo , Doenças dos Peixes/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Intestinos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/genética , Lipase Lipoproteica/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Músculos/metabolismo , Takifugu/crescimento & desenvolvimento , Takifugu/metabolismo , Triglicerídeos/metabolismo , Poluentes Químicos da Água/farmacocinética
18.
J Dairy Sci ; 102(8): 7359-7370, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31155263

RESUMO

Disruption of endoplasmic reticulum (ER) homeostasis, often termed ER stress, is intrinsically linked with perturbation of lipid metabolism in humans and mice. Whether ER homeostasis is affected in cows experiencing fatty liver is unknown. The aim of this study was to investigate the potential role of ER stress in hepatic lipid accumulation in calf hepatocytes and ER stress status in dairy cows with severe fatty liver. In vitro experiments were conducted in which hepatocytes were isolated from calves and treated with different concentrations of fatty acids, tauroursodeoxycholic acid (TUDCA; a canonical inhibitor of ER stress), or both. The increase in phosphorylation level of protein kinase RNA-like ER kinase (PERK) and inositol requiring protein-1α (IRE1α) proteins, and the cleavage of activating transcription factor-6 (ATF6) protein in response to increasing doses of fatty acids (which were reversed by TUDCA treatment) in primary hepatocytes underscored a mechanistic link between fatty acids and ER stress. In addition, fatty acid treatment increased the abundance of sterol regulatory element-binding protein 1c, acetyl-CoA carboxylase-α, fatty acid synthase, and diacylglycerol acyltransferase 1, and lipid accumulation in calf primary hepatocytes, whereas inhibition of ER stress by incubating with TUDCA significantly weakened these effects. Overall, results in vitro indicate that inhibition of ER stress in calf hepatocytes alleviates fatty acid-induced lipid accumulation by downregulating the expression of lipogenic genes. In vivo experiments, liver and blood samples were collected from cows diagnosed as healthy (n = 15) or with severe fatty liver (n = 15). The phosphorylation level of PERK and IRE1α, the cleavage of ATF6 protein, and the abundance of several unfolded protein response genes (78 kDa glucose-regulated protein, AMP-dependent transcription factor 4, and spliced X-box binding protein 1) were greater in liver of cows with severe fatty liver. The present in vivo study confirms the occurrence of ER stress in dairy cows with severe fatty liver. Considering the causative role of fatty acid-induced ER stress in hepatic lipid accumulation in calf hepatocytes, the existence of ER stress in the liver of severe fatty liver cows may presage its participation in fatty liver progression in dairy cows. However, the mechanistic relationship between ER stress and fatty liver in dairy cows remain to be determined.


Assuntos
Doenças dos Bovinos/fisiopatologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ácidos Graxos/administração & dosagem , Fígado Gorduroso/veterinária , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fator 6 Ativador da Transcrição/metabolismo , Animais , Bovinos , Células Cultivadas , Estresse do Retículo Endoplasmático/fisiologia , Endorribonucleases/metabolismo , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Lipogênese/genética , Fígado/efeitos dos fármacos , Camundongos , Fosforilação , Ácido Tauroquenodesoxicólico/administração & dosagem , Resposta a Proteínas não Dobradas/genética , eIF-2 Quinase/metabolismo
19.
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
20.
Mol Cell ; 75(2): 357-371.e7, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31227231

RESUMO

Carbohydrate response element binding protein (ChREBP) is a key transcriptional regulator of de novo lipogenesis (DNL) in response to carbohydrates and in hepatic steatosis. Mechanisms underlying nutrient modulation of ChREBP are under active investigation. Here we identify host cell factor 1 (HCF-1) as a previously unknown ChREBP-interacting protein that is enriched in liver biopsies of nonalcoholic steatohepatitis (NASH) patients. Biochemical and genetic studies show that HCF-1 is O-GlcNAcylated in response to glucose as a prerequisite for its binding to ChREBP and subsequent recruitment of OGT, ChREBP O-GlcNAcylation, and activation. The HCF-1:ChREBP complex resides at lipogenic gene promoters, where HCF-1 regulates H3K4 trimethylation to prime recruitment of the Jumonji C domain-containing histone demethylase PHF2 for epigenetic activation of these promoters. Overall, these findings define HCF-1's interaction with ChREBP as a previously unappreciated mechanism whereby glucose signals are both relayed to ChREBP and transmitted for epigenetic regulation of lipogenic genes.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Proteínas de Homeodomínio/genética , Fator C1 de Célula Hospedeira/genética , Lipogênese/genética , Hepatopatia Gordurosa não Alcoólica/genética , Animais , Carboidratos/genética , Epigênese Genética , Regulação da Expressão Gênica , Glucose/metabolismo , Hexosaminas/genética , Hexosaminas/metabolismo , Humanos , Fígado/metabolismo , Camundongos , Hepatopatia Gordurosa não Alcoólica/patologia , Regiões Promotoras Genéticas/genética , Mapas de Interação de Proteínas/genética
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