RESUMO
The use of essential oils has recently increased in the poultry sector. The aim of this study was to investigate the effects of essential oil mixture (juniper, mint, oregano and rosemary oil) on fatty acid oxidation and lipogenic gene expression in geese. Research groups were formed as C (control; no additives), EK1 (0.4 ml/l essential oil mixture supplemented) and EK2 (0.8 ml/l essential oil mixture supplemented). Relative expression levels of genes included in lipogenesis (ACCα, ChREBP, FASN, LXRα and SREBP-1) expression levels of genes included in fatty acid oxidation (ACOX1, CPT1, CPT1A, PPARα and PPARγ) were measured using RT-qPCR. Group EK1 upregulates the mRNA expression levels of genes involved in lipogenesis such as ACCα, ChREBP and SREBP-1, while it downregulates the mRNA expression in levels of all genes involved in fatty acid oxidation. Group EK2 increases the mRNA expression levels of genes involved in lipogenesis such as ACCα, FASN and SREBP-1, while it decreased mRNA expression at the levels of all genes involved in fatty acid oxidation, as in the other group. In the study, adding an essential oil mixture to drinking water is predicted to increase fatty liver because it upregulates genes related to fat synthesis (lipogenesis) and downregulates genes related to fat degradation (fatty acid oxidation).
Assuntos
Lipogênese , Óleos Voláteis , Animais , Lipogênese/genética , Fígado/metabolismo , Gansos/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Regulação da Expressão Gênica , Ácidos Graxos/metabolismo , RNA Mensageiro/metabolismoRESUMO
Stearic acid (C18:0, SA) is a saturated long-chain fatty acid (LCFA) that has a prominent function in lactating dairy cows. It is obtained primarily from the diet and is stored in the form of triacylglycerol (TAG) molecules. The transmembrane glycoprotein cluster of differentiation 36 (CD36) is also known as fatty acid translocase, but whether SA promotes lipid synthesis through CD36 and FAK/mTORC1 signaling is unknown. In this study, we examined the function and mechanism of CD36-mediated SA-induced lipid synthesis in bovine mammary epithelial cells (BMECs). SA-enriched supplements enhanced lipid synthesis and the FAK/mTORC1 pathway in BMECs. SA-induced lipid synthesis, FAK/mTORC1 signaling, and the expression of lipogenic genes were impaired by anti-CD36 and the CD36-specific inhibitor SSO, whereas overexpression of CD36 effected the opposite results. Inhibition of FAK/mTORC1 by TAE226/Rapamycin attenuated SA-induced TAG synthesis, inactivated FAK/mTORC1 signaling, and downregulated the lipogenic genes PPARG, CD36, ACSL1, SCD, GPAT4, LIPIN1, and DGAT1 at the mRNA and protein levels in BMECs. By coimmunoprecipitation and yeast two-hybrid screen, CD36 interacted directly with Fyn but not Lyn, and Fyn bound directly to FAK; FAK also interacted directly with TSC2. CD36 linked FAK through Fyn, and FAK coupled mTORC1 through TSC2 to form the CD36/Fyn/FAK/mTORC1 signaling axis. Thus, stearic acid promotes lipogenesis through CD36 and Fyn/FAK/mTORC1 signaling in BMECs. Our findings provide novel insights into the underlying molecular mechanisms by which LCFA supplements promote lipid synthesis in BMECs.
Assuntos
Lactação , Lipogênese , Feminino , Bovinos , Animais , Lipogênese/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Glândulas Mamárias Animais/metabolismo , Ácidos Esteáricos/farmacologia , Ácidos Graxos/metabolismo , Células Epiteliais/metabolismoRESUMO
The physiological activity of γ-linolenic acid (GLA)-rich evening primrose oil and eicosapentaenoic and doxosahexaenoic acids-rich fish oil, which affect hepatic fatty acid oxidation and synthesis, and adipose tissue mRNA expression were compared in diabetic obese KK-A y mice. The mice were fed diets containing 100 g/kg of either palm oil (saturated fat), GLA oil, or fish oil for 21 days. These oils, compared with palm oil, greatly increased the activity and mRNA levels of hepatic fatty acid oxidation enzymes. These oils also increased the carnitine concentrations and mRNA levels of carnitine transporter (solute carrier family 22, member 5) in the liver. In general, these effects were comparable between GLA and fish oils. In contrast, GLA and fish oils, compared with palm oil, reduced the activity and mRNA levels of the proteins related to hepatic lipogenesis, except for those of malic enzyme. The reducing effect was stronger for fish oil than for GLA oil. These changes were accompanied by reductions in the triacylglycerol levels in the serum and liver. The reduction in the liver was stronger for fish oil than for GLA oil. These oils also reduced epididymal adipose tissue weight accompanied by a reduction in the mRNA levels of several proteins that regulate adipocyte functions; these effects were stronger for fish oil than for GLA oil. These oils were also effective in reducing serum glucose levels. Therefore, both fish oil and GLA-rich oil were effective at ameliorating metabolic disorders related to obesity and diabetes mellitus.
Assuntos
Óleos de Peixe , Lipogênese , Animais , Camundongos , Tecido Adiposo , Carnitina , Óleos de Peixe/farmacologia , Ácido gama-Linolênico/farmacologia , Lipogênese/genética , Fígado , Óleo de Palmeira , RNA Mensageiro/genéticaRESUMO
Altered lipid metabolism is a hallmark of hepatocellular carcinoma (HCC), a common malignancy with a dismal prognosis against which there is a lack of effective therapeutic strategies. Bufalin, a classical Na[Formula: see text]-K[Formula: see text]-ATPase (NKA) inhibitor, shows a potent antitumor effect against HCC. However, the role of bufalin in regulating lipid metabolism-related pathways of HCC remains unclear. In this study, we examined the interaction between bufalin and its target molecule, ATP1A1/CA2, in vitro and in vivo and explored the intersected downstream pathways in silico. A multi-omics analysis of transcriptomics and metabolomics was employed to screen for potential action targets. The results were verified and correlated with the downstream lipid de novo synthesis pathway and the bufalin/ATP1A1/CA2 axis. We found that bufalin suppressed the ATP1A1/CA2 ratio in the treated HCC cells and showed a negative correlation with bufalin drug sensitivity. Functionally, ATP1A1 overexpression and CA2 down-regulation inhibited the bufalin-suppressed HCC proliferation and metastasis. Furthermore, down-regulation of CA2 induced epithelial-mesenchymal transition and bufalin resistance in HCC cells by up-regulating ATP1A1. Mechanistically, lipid metabolism-related signaling pathways were enriched in low ATP1A1 and high CA2 expression subgroups in GSEA. The multi-omics analysis also showed that bufalin was closely related to lipid metabolism. We demonstrated that bufalin inhibits lipogenesis and tumorigenesis by down-regulating SREBP-1/FASN/ACLY via modulating the ATP1A1/CA2 axis in HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Lipogênese/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proliferação de Células/genética , Transformação Celular Neoplásica , Carcinogênese/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , ATPase Trocadora de Sódio-Potássio/metabolismoRESUMO
Accumulating evidence suggests that de novo lipogenesis is a typical characteristic facilitating nonalcoholic fatty liver disease (NAFLD) progression. Gallic acid (GA) is a naturally occurring phenolic acid with metabolic disease-related clinical significance and preclinical benefits. This study aimed to evaluate the anti-steatotic potentials of GA in a fructose-induced NAFLD mouse model featuring a hepatic lipogenic phenotype. The results revealed that GA alleviated hepatic steatosis, oxidative stress, and inflammatory response in fructose-fed mice. Mechanistically, GA treatment restored AMP-activated protein kinase α (AMPKα) phosphorylation, resulting in downregulations of pro-lipogenic factors, including sterol regulatory element binding protein-1 (SREBP-1), fatty acid synthetase (FASN), and acetyl-CoA carboxylase (ACC), in hepatocytes of mice and in vitro. Furthermore, computational docking analysis indicated that GA could directly interact with AMPKα/ß subunits to stabilize its activation. These results suggest that GA ameliorates fructose-induced hepatosteatosis by restraining hepatic lipogenesis via AMPK-dependent suppression of the SREBP-1/ACC/FASN cascade. Altogether, this study demonstrates that GA supplement may be a promising therapeutic strategy in NAFLD, especially in the subset with enhanced hepatic lipogenesis.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Lipogênese/genética , Acetil-CoA Carboxilase/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Ácidos Graxos/metabolismo , Ligases/metabolismo , Ácido Gálico/farmacologia , Ácido Gálico/uso terapêutico , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Frutose/efeitos adversos , Fígado/metabolismo , Ácido Graxo Sintase Tipo I/metabolismoRESUMO
Mounting evidence showed that excess selenium (10.0-15.0-fold of adequate Se) intake caused severe hepatic lipid deposition in the vertebrate. However, the underlying mechanism remains unclear. The study was performed to elucidate the mechanism of Se supranutrition mediated-changes of lipid deposition and metabolism. We found that dietary excessive Se addition increased hepatic TGs and glucose contents, up-regulated lipogenic enzyme activities and reduced hepatic glycogen contents. Transcriptomic and immunoblotting analysis showed that Se supranutrition significantly influenced serine/threonine kinase 1 (AKT1)-forkhead box O3a (FOXO3a)-PYGL signaling and protein levels of SELENOF. Knockdown of SELENOF and PYGL by RNA interference revealed that the AKT1-FOXO3a-PYGL axis was critical for Se supranutrition-induced lipid accumulation. Moreover, Se supranutrition-induced lipid accumulation was via the increased DNA binding capacity of FOXO3a to PYGL promoter, which increased glycogenolysis, and accordingly promoted lipogenesis and lipid accumulation. Our finding provides new insight into the mechanism of Se supranutrition-induced lipid accumulation and suggests that SELENOF may be a therapeutic target for Se supranutrition induced-lipid disorders in the vertebrates.
Assuntos
Glicogenólise , Selênio , Animais , Lipídeos , Lipogênese/genética , Selênio/farmacologia , Selenoproteínas/genéticaRESUMO
Obesity promotes the development of osteoarthritis (OA). It is also well-established that obesity leads to excessive lipid deposition in nonadipose tissues, which often induces lipotoxicity. The objective of this study was to investigate changes in the levels of various lipids in mouse cartilage in the context of obesity and determine if chondrocyte de novo lipogenesis is altered. We used Oil Red O to determine the accumulation of lipid droplets in cartilage from mice fed high-fat diet (HFD) or low-fat diet (LFD). We further used mass spectrometry-based lipidomic analyses to quantify levels of different lipid species. Expression of genes involving in fatty acid (FA) uptake, synthesis, elongation, and desaturation were examined using quantitative polymerase chain reaction. To further study the potential mechanisms, we cultured primary mouse chondrocytes under high-glucose and high-insulin conditions to mimic the local microenvironment associated with obesity and subsequently examined the abundance of cellular lipid droplets. The acetyl-CoA carboxylase (ACC) inhibitor, ND-630, was added to the culture medium to examine the effect of inhibiting de novo lipogenesis on lipid accumulation in chondrocytes. When compared to the mice receiving LFD, the HFD group displayed more chondrocytes with visible intracellular lipid droplets. Significantly higher amounts of total FAs were also detected in the HFD group. Five out of six significantly upregulated FAs were ω-6 FAs, while the two significantly downregulated FAs were ω-3 FAs. Consequently, the HFD group displayed a significantly higher ω-6/ω-3 FA ratio. Ether linked phosphatidylcholine was also found to be higher in the HFD group. Fatty acid desaturase (Fad1-3), fatty acid-binding protein 4 (Fabp4), and fatty acid synthase (Fasn) transcripts were not found to be different between the treatment groups and fatty acid elongase (Elovl1-7) transcripts were undetectable in cartilage. Ceramide synthase 2 (Cers-2), the only transcript found to be changed in these studies, was significantly upregulated in the HFD group. In vitro, chondrocytes upregulated de novo lipogenesis when cultured under high-glucose, high-insulin conditions, and this observation was associated with the activation of ACC, which was attenuated by the addition of ND-630. This study provides the first evidence that lipid deposition is increased in cartilage with obesity and that this is associated with the upregulation of ACC-mediated de novo lipogenesis. This was supported by our observation that ACC inhibition ameliorated lipid accumulation in chondrocytes, thereby suggesting that ACC could potentially be targeted to treat obesity-associated OA.
Assuntos
Ácidos Graxos Ômega-3 , Insulinas , Camundongos , Animais , Lipogênese/genética , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Acetil-CoA Carboxilase/farmacologia , Condrócitos/metabolismo , Fígado/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Dieta Hiperlipídica/efeitos adversos , Glucose/metabolismo , Insulinas/metabolismo , Insulinas/farmacologiaRESUMO
Obesity is a health and medical problem and is known as the accumulation of fat that increases the risk of cardiovascular, type 2 diabetes mellitus, and infertility. Cinnamon is a spice that is used mainly as a flavoring additive and folk remedies to treat diabetes. Molecular mechanisms of its effects on hepatic lipogenesis and beta-oxidation, inflammation, and oxidative damage are not fully understood. Therefore, the aim of this study was to evaluate the protective and therapeutic effect of different doses of cinnamon in obese male rats. Forty-eight adult male Wister rats were randomly assigned into eight controlled and treated groups. Serum levels of lipid, glucose, and insulin profiles were measured along with liver levels of antioxidant enzymes, MDA and TNF-α. Hepatic expression of genes involved in beta-oxidation, lipogenesis, oxidative stress, and inflammation was also evaluated. Hepatic levels of oxidative and inflammatory biomarkers and serum levels of glucose, liver enzymes, insulin, and lipid profiles increased significantly in obese rats. Moreover, hepatic expression of SREBP-1c and NF-κB increased, and PPAR-alpha, CD36, FAS, CPT-1, and Nrf-2 decreased in obese rats. However, pretreatment and treatment with different doses of cinnamon in obese rats could significantly ameliorate them in obese rats. It can be concluded that cinnamon could improve hepatic steatosis caused by a high-fat diet via enhancing hepatic beta-oxidation and inhibiting hepatic lipogenesis, oxidative damage, and inflammation in male rats. PRACTICAL APPLICATIONS: Obesity as a medical and psychiatric problem is seen in more than a third of the world's population. Obesity leads to cardiovascular disease, diabetes, and in some cases even death. Cinnamon as a spice and folk remedy has long been used as a treatment for obesity and liver disease. Cinnamon has received a great of attention from the past to the present due to its pharmacological properties and in addition to its availability, cheapness and low side effects. Cinnamon can prevent dyslipidemia, hyperglycemia, oxidative damage, and inflammation by modulating multiple signaling pathways. Our results showed that cinnamon could improve hepatic steatosis caused by HFD via enhancing hepatic beta-oxidation and inhibiting hepatic lipogenesis, oxidative damage, and inflammation. Therefore, it can be recommended that cinnamon and its products can be used as a very suitable option for the production of pharmaceutical supplements for the prevention and treatment of metabolic diseases.
Assuntos
Diabetes Mellitus Tipo 2 , Fígado Gorduroso , Animais , Cinnamomum zeylanicum/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/etiologia , Glucose/metabolismo , Inflamação/tratamento farmacológico , Insulina , Lipídeos , Lipogênese/genética , Masculino , Obesidade/complicações , Obesidade/etiologia , Estresse Oxidativo , Ratos , Ratos WistarRESUMO
Obesity is a public health problem characterized by increased body weight due to abnormal adipose tissue expansion. Bioactive compound consumption from the diet or intake of dietary supplements is one of the possible ways to control obesity. Natural products with adipogenesis-regulating potential act as obesity treatments. We evaluated the synergistic antiangiogenesis, antiadipogenic and antilipogenic efficacy of standardized rebaudioside A, sativoside, and theasaponin E1 formulations (RASE1) in vitro in human umbilical vein endothelial cells (HUVECs), 3T3-L1 preadipocytes respectively, and in vivo using a high-fat and carbohydrate diet-induced obesity mouse model. Orlistat was used as a positive control, while untreated cells and animals were normal controls (NCs). Adipose tissue, liver, and blood were analyzed after dissection. Extracted stevia compounds and green tea seed saponin E1 exhibited pronounced antiobesity effects when combined. RASE1 inhibited HUVEC proliferation and tube formation by suppressing VEGFR2, NF-κB, PIK3, and-catenin beta-1 expression levels. RASE1 inhibited 3T3-L1 adipocyte differentiation and lipid accumulation by downregulating adipogenesis- and lipogenesis-promoting genes. RASE1 oral administration reduced mouse body and body fat pad weight and blood cholesterol, TG, ALT, AST, glucose, insulin, and adipokine levels. RASE1 suppressed adipogenic and lipid metabolism gene expression in mouse adipose and liver tissues and enhanced AMP-activated protein kinase levels in liver and adipose tissues and in serum adiponectin. RASE1 suppressed the NF-κB pathway and proinflammatory cytokines IL-10, IL-6, and TNF-α levels in mice which involve inflammation and progression of obesity. The overall results indicate RASE1 is a potential therapeutic formulation and functional food for treating or preventing obesity and inflammation.
Assuntos
Produtos Biológicos/uso terapêutico , Inflamação/tratamento farmacológico , Obesidade/tratamento farmacológico , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Adipogenia/genética , Inibidores da Angiogênese/uso terapêutico , Animais , Produtos Biológicos/administração & dosagem , Produtos Biológicos/toxicidade , Modelos Animais de Doenças , Diterpenos do Tipo Caurano/administração & dosagem , Composição de Medicamentos , Sinergismo Farmacológico , Feminino , Glucosídeos/administração & dosagem , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Lipólise/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Obesidade/genética , Obesidade/metabolismo , Ácido Oleanólico/administração & dosagem , Ácido Oleanólico/análogos & derivados , Fitoterapia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Saponinas/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Stevia/química , Chá/químicaRESUMO
Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disorder that causes excess lipid accumulation in the liver and is the leading cause of end-stage liver disease. Liriope platyphylla is a medicinal herb that has long been used to treat cough, obesity, and diabetes. However, the effect of Liriope platyphylla on NAFLD has not been studied. The aim of this study was to investigate the effect of Liriope platyphylla root ethanolic extract (LPE) on hepatic lipid accumulation in high-fat diet (HFD)-induced obese mice. Six-week-old C57BL/6 male mice were fed a HFD for 8 weeks and then treated with LPE (100 or 250 mg/kg/day) by oral gavage for another 8 weeks. Body weight gain and liver weight were significantly lower in the 250 mg/kg LPE-treated HFD group than in the vehicle-treated HFD group. Histological analysis of liver sections demonstrated that LPE treatment reduced lipid accumulation compared to the vehicle treatment. The serum total cholesterol, AST, and ALT levels significantly decreased in the LPE-treated HFD group compared to those in the vehicle-treated HFD group. The LPE significantly decreases the protein expression levels of SREBP1, ACC, p-ACC, FAS, and SCD1, which are involved in lipogenesis, and PPARγ, CD36/FAT, and FATP5, which are involved in fatty acid uptake, both in vivo and in vitro. Thus, LPE may attenuate HFD-induced NAFLD by decreasing lipid accumulation by inhibiting lipogenesis and fatty acid uptake.
Assuntos
Dieta Hiperlipídica , Etanol/química , Lipídeos/sangue , Lipogênese , Liriope (Planta)/química , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Raízes de Plantas/química , Animais , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica , Células Hep G2 , Humanos , Lipogênese/genética , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos , Extratos Vegetais/farmacologia , Triglicerídeos/sangue , Aumento de PesoRESUMO
Cyperus esculentus is widely representing one of the important oil crops around the world, which provides valuable resources of edible tubers called tiger nut. The chemical composition and high ability to produce fats emphasize the role of tiger nut in promoting oil crop productivity. However, the underlying molecular mechanism of the production and accumulation of lipids in tiger nut development still remains unclear. Here, we conducted comprehensive transcriptomics and lipidomics analyses at different developmental stages of tuber in Cyperus esculentus. Lipidomic analyses confirmed that the accumulation of lipids including glycolipids, phospholipids, and glycerides were significantly enriched during tuber development from early to mature stage. The proportion of phosphatidylcholines (PC) declined during all stages and phosphatidyl ethanolamine (PE) was significantly declined in early and middle stages. These findings implied that PC is actively involved in triacylglycerol (TAG) biosynthesis during the tubers development, whereas PE may participate in TAG metabolism during early and middle stages. Comparative transcriptomics analyses indicated several genomic and metabolic pathways associated with lipid metabolism during tuber development in tiger nut. The Pearson correlation analysis showed that TAG synthesis in different developmental stages was attributed to 37 candidate transcripts including CePAH1. The up-regulation of diacylglycerol (DAG) and oil content in yeast, resulted from the inducible expression of exogenous CePAH1 confirmed the central role of this candidate gene in lipid metabolism. Our results demonstrated the foundation of an integrative metabolic model for understanding the molecular mechanism of tuber development in tiger nut, in which lipid biosynthesis plays a central role.
Assuntos
Cyperus/genética , Lipídeos/biossíntese , Tubérculos/genética , Transcriptoma/genética , Cyperus/crescimento & desenvolvimento , Regulação da Expressão Gênica de Plantas/genética , Metabolismo dos Lipídeos/genética , Lipidômica , Lipídeos/genética , Lipogênese/genética , Desenvolvimento Vegetal/genética , Óleos de Plantas/metabolismo , Tubérculos/crescimento & desenvolvimentoRESUMO
Excessive liver lipid deposition is a vital risk factor for the development of many diseases. Here, we fed Sprague-Dawley rats with a control or α-lipoic acid-supplemented diet (0.2%) for 5 weeks to elucidate the effects of α-lipoic acid on preventive ability, hepatic lipid metabolism-related gene expression, and the involved regulatory mechanisms. In the current study, α-lipoic acid supplementation lowered plasma triglyceride level and hepatic triglyceride content. Reduced hepatic lipid deposition was closely associated with inhibiting fatty acid-binding protein 1 and fatty acid synthase expression, as well as increasing phosphorylated hormone-sensitive lipase expression at the protein level in α-lipoic acid-exposed rats. Hepatic miRNA sequencing revealed increased expression of miR-3548 targeting the 3'untranslated region of Fasn mRNA, and the direct regulatory link between miRNA-3548 and FASN was verified by dual-luciferase reporter assay. Taken together, α-lipoic acid lowered hepatic lipid accumulation, which involved changes in miRNA-mediated lipogenic genes.
Assuntos
Suplementos Nutricionais , Ácido Graxo Sintase Tipo I/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , MicroRNAs/metabolismo , Ácido Tióctico/farmacologia , Animais , Ácido Graxo Sintases/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Expressão Gênica/efeitos dos fármacos , Lipogênese/genética , Fígado/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Triglicerídeos/metabolismoRESUMO
BACKGROUND AND AIMS: Butyric acid is an intestinal microbiota-produced short-chain fatty acid, which exerts salutary effects on alleviating nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanism of butyrate on regulating hepatic lipid metabolism is largely unexplored. METHODS: A mouse model of NAFLD was induced with high-fat diet feeding, and sodium butyrate (NaB) intervention was initiated at the eighth week and lasted for 8 weeks. Hepatic steatosis was evaluated and metabolic pathways concerning lipid homeostasis were analyzed. RESULTS: Here, we report that administration of NaB by gavage once daily for 8 weeks causes an augmentation of insulin-induced gene (Insig) activity and inhibition of lipogenic gene in mice fed with high-fat diet. Mechanistically, NaB is sufficient to enhance the interaction between Insig and its upstream kinase AMP-activated protein kinase (AMPK). The stimulatory effects of NaB on Insig-1 activity are abolished in AMPKα1/α2 double knockout (AMPK-/-) mouse primary hepatocytes. Moreover, AMPK activation by NaB is mediated by LKB1, as evidenced by the observations showing NaB-mediated induction of phosphorylation of AMPK, and its downstream target acetyl-CoA carboxylase is diminished in LKB1-/- mouse embryonic fibroblasts. CONCLUSIONS: These studies indicate that NaB serves as a negative regulator of hepatic lipogenesis in NAFLD and that NaB attenuates hepatic steatosis and improves lipid profile and liver function largely through the activation of LKB1-AMPK-Insig signaling pathway. Therefore, NaB has therapeutic potential for treating NAFLD and related metabolic diseases.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Ácido Butírico/farmacologia , Suplementos Nutricionais , Regulação da Expressão Gênica , Insulina/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Insulina/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Modelos Biológicos , Hepatopatia Gordurosa não Alcoólica/patologia , FosforilaçãoRESUMO
Annona muricata (graviola) is a medicinal plant that can be used to alleviate chronic human diseases by providing antioxidants and inducing immunomodulation. In this study, we found that treatment of AML12 hepatocytes with steam (SGE) and ethanol (EGE) extracts of graviola leaf downregulated the expression of fatty acid (FA) oxidation genes, including ACOX1, CPT1, and PPARα, with no change in the expression of FA synthesis genes. However, whereas EGE inhibited the differentiation and lipid accumulation of 3T3-L1 adipocytes and downregulated FA synthesis genes, no similar changes were observed in response to treatment with SGE. In an in vivo experiment using mice fed a high-fat diet (HFD), body weight was reduced in response to treatment with EGE, which also dose-dependently alleviated liver hepatocyte ballooning induced by the consumption of a HFD. However, genes involved in FA oxidation and the secretion of very low density lipoprotein (VLDL) were downregulated. We also found that the size of adipocytes was reduced in response to EGE treatment, and that there was a downregulated expression of genes involved in adipogenesis and FA synthesis. Furthermore, we detected increases in the levels of cholesterol in the plasma, whereas ALT activity was reduced. Collectively, these results indicates that EGE inhibits lipid influx into the liver and adipogenesis in adipose tissues. These bioactive properties of EGE indicate its potential as a natural ingredient that can be used to prevent obesity.
Assuntos
Adipogenia/efeitos dos fármacos , Annona/química , Lipogênese/efeitos dos fármacos , Fígado/metabolismo , Extratos Vegetais/farmacologia , Células 3T3-L1 , Acil-CoA Oxidase/genética , Adipócitos/metabolismo , Adipogenia/genética , Animais , Diferenciação Celular/efeitos dos fármacos , Dieta Hiperlipídica , Regulação para Baixo , Regulação da Expressão Gênica/efeitos dos fármacos , Metabolismo dos Lipídeos , Lipogênese/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , PPAR alfaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Diabetes mellitus (DM), as a multiorgan syndrome, is an endocrine and metabolic disorder that is associated with male reproductive system dysfunction and infertility. Safflower (Carthamus tinctorius L.) as an herbal remedy improves DM and infertility-related disorders. The anti-hypercholesterolemic, anti-inflammatory, and antioxidative properties of this herb have been well documented, but its role in testosterone production, male reproductive system and zinc homeostasis has not been fully illustrated. AIM OF THE STUDY: This study aimed to investigate the preventive and therapeutic properties of different doses of safflower seed oil against reproductive damage caused by type II DM by investigating zinc element homeostasis, inflammation and oxidative damage in testis tissue and their relationship with testosterone production and sperm parameters. MATERIALS AND METHODS: Eighty adult male Sprague-Dawley rats were randomly divided into eight groups and treated daily for 12 and 24 weeks in protective and therapeutic studies, respectively. Type II DM was induced by a High Fat Diet (HFD) in normoglycemic rats for three months. At the end of each study, serum level of glucose, testosterone, gonadotropins, TNF-α, insulin, and leptin were measured. Moreover, antioxidant enzymes activity, lipid peroxidation, zinc and testosterone along with the expression of Nrf-2, NF-κB, TNF-α, StAR, P450scc, and 17ßHSD3 genes in the testis were detected. RESULTS: After the intervention, the activity of antioxidant enzymes and the level of testosterone and gonadotropins significantly decreased in the rats with DM in comparison to the others. However, lipid peroxidation and serum level of insulin, leptin and TNF-α increased and the testicular level of zinc significantly changed in the rats with DM compared to the control groups (p < 0.05). The gene expression of NF-κB and TNF-α were also significantly increased and the gene expression of Nrf2, StAR, P450scc and 17ßHSD3 were decreased in the testis of diabetic rats (p < 0.05). The results showed that pretreatment and treatment with safflower seed oil could improve these parameters in diabetic rats compared with untreated diabetic rats (p < 0.05). CONCLUSION: HFD could impair the production of testosterone and sperm, and reduce gonadotropin by increasing the serum level of leptin and inducing insulin resistance, oxidative stress and inflammation. However, safflower oil in a dose-dependent manner could improve testosterone level and sperm parameters by improving the level of leptin, zinc and insulin resistance, and the genes expression involved in testosterone synthesis, inflammation and oxidative stress.
Assuntos
Antioxidantes/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Inflamação/genética , Lipogênese/genética , Estresse Oxidativo/genética , Óleo de Cártamo/farmacologia , Espermatogênese/genética , Animais , Antioxidantes/análise , Antioxidantes/uso terapêutico , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2 , Dieta Hiperlipídica/efeitos adversos , Ingestão de Alimentos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Gonadotropinas/sangue , Inflamação/metabolismo , Insulina/sangue , Leptina/sangue , Peroxidação de Lipídeos/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Óleo de Cártamo/química , Óleo de Cártamo/uso terapêutico , Sementes/química , Espermatogênese/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Esteroides/metabolismo , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia , Testosterona/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Zinco/sangueRESUMO
BACKGROUND: Paeonia ostii seeds were identified as novel sources of edible plant oil with a high proportion of α-linolenic acid, a type of n-3 fatty acid with many health benefits. Due to the unreliability of seed oil content and quality, it is necessary to discover the mechanism underlying lipid biosynthesis in Paeonia ostii seeds. OBJECTIVES: This study aimed to identify the key genes involved in lipid biosynthesis in Paeonia ostii seeds by analyzing the relationship among the seed characteristics and the expression patterns of lipid genes in Paeonia ostii during seed development. METHODS: Preliminary research on Paeonia ostii seed development was carried out from 10 days after pollination until maturity, focusing on phenology, oil content and lipid profiles. In addition, we investigated the spatiotemporal expression of 36 lipid biosynthetic genes in Paeonia ostii by using quantitative real-time PCR. RESULTS: The results suggested that the development of Paeonia ostii seeds from pollination to maturity could be divided into three periods. The 36 lipid genes showed various spatiotemporal expression patterns and five gene groups with distinct temporal patterns during seed development were identified by clustering analysis of expression data. Furthermore, the relationships between gene expression and lipid/fatty acid accumulation and some candidate key lipid genes were discussed. CONCLUSIONS: This study provided the global patterns of fatty acid and lipid biosynthesis-related gene expression, which are critical to understanding the molecular basis of lipid biosynthesis and identifying the lipid accumulation rate-limiting genes during seed development.
Assuntos
Ácidos Graxos/genética , Lipídeos/biossíntese , Paeonia/genética , Sementes/genética , Regulação da Expressão Gênica de Plantas/genética , Lipídeos/genética , Lipogênese/genética , Paeonia/crescimento & desenvolvimento , Sementes/crescimento & desenvolvimento , Transcriptoma/genéticaRESUMO
Carnosic acid (CA), carnosol (CL) and rosmarinic acid (RA), components of the herb rosemary, reportedly exert favorable metabolic actions. This study showed that both CA and CL, but not RA, induce significant phosphorylation of AMP-dependent kinase (AMPK) and its downstream acetyl-CoA carboxylase 1 (ACC1) in HepG2 hepatoma cells. Glucose-6-phosphatase (G6PC) and phosphoenolpyruvate carboxykinase 1 (PCK1), rate-limiting enzymes of hepatic gluconeogenesis, are upregulated by forskolin stimulation, and this upregulation was suppressed when incubated with CA or CL. Similarly, a forskolin-induced increase in CRE transcriptional activity involved in G6PC and PCK1 regulations was also stymied when incubated with CA or CL. In addition, mRNA levels of ACC1, fatty acid synthase (FAS) and sterol regulatory element-binding protein 1c (SREBP-1c) were significantly reduced when incubated with CA or CL. Finally, it was shown that CA and CL suppressed cell proliferation and reduced cell viability, possibly as a result of AMPK activation. These findings raise the possibility that CA and CL exert a protective effect against diabetes and fatty liver disease, as well as subsequent cases of hepatoma.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Abietanos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Gluconeogênese/genética , Lipogênese/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Ácidos Graxos/biossíntese , Gluconeogênese/efeitos dos fármacos , Células HEK293 , Células Hep G2 , Humanos , Lipogênese/efeitos dos fármacos , Camundongos , Oxirredução , Fosforilação/efeitos dos fármacos , Extratos Vegetais/farmacologia , Rosmarinus/química , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genéticaRESUMO
Obesity and aging are associated to non-alcoholic fatty liver disease (NAFLD) development. Here, we investigate whether long-term feeding with a docosahexaenoic acid (DHA)-enriched diet and aerobic exercise, alone or in combination, are effective in ameliorating NAFLD in aged obese mice. Two-month-old female C57BL/6J mice received control or high fat diet (HFD) for 4 months. Then, the diet-induced obese (DIO) mice were distributed into four groups: DIO, DIO + DHA (15% dietary lipids replaced by a DHA-rich concentrate), DIO + EX (treadmill running), and DIO + DHA + EX up to 18 months. The DHA-rich diet reduced liver steatosis in DIO mice, decreasing lipogenic genes (Dgat2, Scd1, Srebp1c), and upregulated lipid catabolism genes (Hsl/Acox) expression. A similar pattern was observed in the DIO + EX group. The combination of DHA + exercise potentiated an increase in Cpt1a and Ppara genes, and AMPK activation, key regulators of fatty acid oxidation. Exercise, alone or in combination with DHA, significantly reversed the induction of proinflammatory genes (Mcp1, Il6, Tnfα, Tlr4) in DIO mice. DHA supplementation was effective in preventing the alterations induced by the HFD in endoplasmic reticulum stress-related genes (Ern1/Xbp1) and autophagy markers (LC3II/I ratio, p62, Atg7). In summary, long-term DHA supplementation and/or exercise could be helpful to delay NAFLD progression during aging in obesity.
Assuntos
Envelhecimento/fisiologia , Ácidos Docosa-Hexaenoicos/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Obesidade/complicações , Condicionamento Físico Animal/fisiologia , Animais , Autofagia/genética , Autofagia/fisiologia , Dieta Hiperlipídica , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Inflamação/genética , Metabolismo dos Lipídeos , Lipogênese/genética , Fígado/química , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/genética , Obesidade/etiologia , RNA Mensageiro/análiseRESUMO
Citrus fruits contain an abundance of nutrients, including vitamins C and B6 and hesperidin, which attribute to its beneficial health effects. Previously, kimchi with Jeju citrus concentrate (CK) elicited anti-obesity effects in 3T3-L1 adipocytes. Here, we aimed to investigate whether CK exhibits anti-obesity effects by reducing serum and hepatic lipid concentrations and anti-obesity-associated gene expression in high-fat diet (HFD)-induced obese C57BL/6N mice. Low-dose CK (LDCK, 50 mg/kg) and high-dose CK (HDCK, 200 mg/kg) were orally administered 3 times per week over 8 weeks with HFD diet. Body weight gain, food efficiency ratio, and tissue weight were measured. Serum glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, fasting glucose, fasting insulin, homeostatic model assessment-insulin resistance, leptin, and adiponectin concentrations were also assessed. The effect of CK on the lipid profile and lipid accumulation was analyzed. Body and white adipose tissue masses were significantly lower in the LDCK and HDCK groups than in the HFD group. Orally administered CK significantly decreased serum lipid, fasting glucose, fasting insulin, homeostatic model assessment-insulin resistance, glutamic oxaloacetic transaminase, and glutamic pyruvic transaminase levels. Hepatic lipid content also decreased in the LDCK and HDCK groups. Serum leptin concentrations decreased, whereas serum adiponectin concentrations increased, confirming the anti-obesity effects of LDCK and HDCK. The decrease of hepatic vacuoles and stained lipid droplets indicated inhibition of lipid accumulation. These results support the hypothesis that CK exhibits anti-obesity effects in vivo by reducing lipid accumulation and by regulating anti-obesity-related genes.
Assuntos
Citrus , Dieta Hiperlipídica/efeitos adversos , Alimentos Fermentados , Frutas , Metabolismo dos Lipídeos , Obesidade/dietoterapia , Adipogenia/genética , Adiponectina/sangue , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Peso Corporal , Regulação da Expressão Gênica , Resistência à Insulina , Leptina/sangue , Lipídeos/sangue , Lipogênese/genética , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/metabolismoRESUMO
The present study investigated the influence of berberine (BBR) supplementation in normal and high-lipid (HL) diets on lipid metabolism and accumulation in black sea bream (Acanthopagrus schlegelii). BBR was supplemented at 50 mg/kg to control (Con, 11·1 % crude lipid) and high-lipid (HL, 20·2 % crude lipid) diets and named as ConB and HLB, respectively. After the 8-week feeding trial, fish body length and specific growth rate were significantly reduced by HL diets (P < 0·05). Muscle and whole-body crude lipid contents were significantly influenced by both BBR supplementation and dietary lipid level. Fish fed the HLB diet had significantly lower serum TAG, LDL-cholesterol contents and alanine aminotransferase activity compared with the HL group. The HL group presented vast lipid accumulation in the liver, and hypertrophied hepatocytes along with large lipid droplets, and translocation of nuclear to the cell periphery. These abnormalities in black sea bream were alleviated in the HLB group. BBR supplementation in the HL diet significantly down-regulated the hepatic expression levels of acetyl-CoA carboxylase α, sterol regulatory element-binding protein-1, 6-phosphogluconate dehydrogenase, glucose 6-phosphate dehydrogenase and pparγ, whereas the lipoprotein lipase, hormone-sensitive lipase and carnitine palmitoyltransferase 1a expression levels were significantly up-regulated. However, the expression levels of these genes showed opposite trends in muscle (except for pparγ). In conclusion, dietary BBR supplementation in the HL diet reduced hepatic lipid accumulation by down-regulating lipogenesis gene expression and up-regulating lipolysis gene expression, and it increased muscle lipid contents with opposite trends of the mechanism observed in the liver.