RESUMO
This study investigated the antitumoral, anti-inflammatory and oxidative effects of polysaccharides from tucum (Bactris setosa, TUC) using the Ehrlich carcinoma as a tumor model. Additionally, the glycogen content, cytochrome P levels, and gluconeogenesis from lactate were assessed in the liver of healthy animals. Tumor-bearing female mice were orally treated with 50 and 100 mg.kg-1 of TUC or vehicle, once a day, or with 1.5 mg.kg-1 methotrexate via i.p., every 3 days, along 21 days. Both doses of TUC reduced the tumor weight and volume. In the tumor tissue, it decreased GSH and IL-1ß levels, and increased LPO, NAG, NO and TNF-α levels. The tumor histology showed necrosis and leukocytes infiltration. The metabolic effects of TUC were investigated by measurement of total cytochrome P (CYP) and glycogen in tumor-bearing mice, and by ex vivo liver perfusion on non-bearing tumor male mice, using lactate as gluconeogenic precursor. Metabolically, the hepatic glucose and pyruvate productions, oxygen uptake, and the total CYP concentration were not modified by TUC. Thus, tucum-do-cerrado polysaccharides have antitumor effects through the modulation of oxidative stress and inflammation, without impairing glucose production from lactate in the liver, the main organ responsible for the metabolism of organic and xenobiotic compounds.
Assuntos
Gluconeogênese , Fígado , Polissacarídeos , Animais , Polissacarídeos/farmacologia , Polissacarídeos/química , Camundongos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Gluconeogênese/efeitos dos fármacos , Feminino , Masculino , Antineoplásicos/farmacologia , Antineoplásicos/química , Estresse Oxidativo/efeitos dos fármacos , Frutas/química , Glicogênio/metabolismo , Carcinoma de Ehrlich/tratamento farmacológico , Carcinoma de Ehrlich/patologia , Carcinoma de Ehrlich/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/químicaRESUMO
BACKGROUND AND AIM: Although it is well established that hormones like glucagon stimulates gluconeogenesis via the PKA-mediated phosphorylation of CREB and dephosphorylation of the cAMP-regulated CREB coactivators CRTC2, the role of neural signals in the regulation of gluconeogenesis remains uncertain. METHODS AND RESULTS: Here, we characterize the noradrenergic bundle architecture in mouse liver; we show that the sympathoexcitation induced by acute cold exposure promotes hyperglycemia and upregulation of gluconeogenesis via triggering of the CREB/CRTC2 pathway. Following its induction by dephosphorylation, CRTC2 translocates to the nucleus and drives the transcription of key gluconeogenic genes. Rodents submitted to different models of sympathectomy or knockout of CRTC2 do not activate gluconeogenesis in response to cold. Norepinephrine directly acts in hepatocytes mainly through a Ca2+-dependent pathway that stimulates CREB/CRTC2, leading to activation of the gluconeogenic program. CONCLUSION: Our data demonstrate the importance of the CREB/CRTC2 pathway in mediating effects of hepatic sympathetic inputs on glucose homeostasis, providing new insights into the role of norepinephrine in health and disease.
Assuntos
Temperatura Baixa , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Gluconeogênese , Fígado , Norepinefrina , Fatores de Transcrição , Animais , Gluconeogênese/fisiologia , Fígado/metabolismo , Camundongos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Masculino , Norepinefrina/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Neurônios Adrenérgicos/metabolismo , Neurônios Adrenérgicos/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/fisiologia , Hepatócitos/metabolismoRESUMO
BACKGROUND: Aberrant gluconeogenesis is considered among primary drivers of hyperglycemia under insulin resistant conditions, with multiple studies pointing towards epigenetic dysregulation. Here we examine the role of miR-721 and effect of epigenetic modulator laccaic acid on the regulation of gluconeogenesis under high fat diet induced insulin resistance. RESULTS: Reanalysis of miRNA profiling data of high-fat diet-induced insulin-resistant mice model, GEO dataset (GSE94799) revealed a significant upregulation of miR-721, which was further validated in invivo insulin resistance in mice and invitro insulin resistance in Hepa 1-6 cells. Interestingly, miR-721 mimic increased glucose production in Hepa 1-6 cells via activation of FOXO1 regulated gluconeogenic program. Concomitantly, inhibition of miR-721 reduced glucose production in palmitate induced insulin resistant Hepa 1-6 cells by blunting the FOXO1 induced gluconeogenesis. Intriguingly, at epigenetic level, enrichment of the transcriptional activation mark H3K36me2 got decreased around the FOXO1 promoter. Additionally, identifying targets of miR-721 using miRDB.org showed H3K36me2 demethylase KDM2A as a potential target. Notably, miR-721 inhibitor enhanced KDM2A expression which correlated with H3K36me2 enrichment around FOXO1 promoter and the downstream activation of the gluconeogenic pathway. Furthermore, inhibition of miR-721 in high-fat diet-induced insulin-resistant mice resulted in restoration of KDM2A levels, concomitantly reducing FOXO1, PCK1, and G6PC expression, attenuating gluconeogenesis, hyperglycemia, and improving glucose tolerance. Interestingly, the epigenetic modulator laccaic acid also reduced the hepatic miR-721 expression and improved KDM2A expression, supporting our earlier report that laccaic acid attenuates insulin resistance by reducing gluconeogenesis. CONCLUSION: Our study unveils the role of miR-721 in regulating gluconeogenesis through KDM2A and FOXO1 under insulin resistance, pointing towards significant clinical and therapeutic implications for metabolic disorders. Moreover, the promising impact of laccaic acid highlights its potential as a valuable intervention in managing insulin resistance-associated metabolic diseases.
Assuntos
Gluconeogênese , Resistência à Insulina , Histona Desmetilases com o Domínio Jumonji , MicroRNAs , Animais , Masculino , Camundongos , Dieta Hiperlipídica , Epigênese Genética , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O1/genética , Gluconeogênese/genética , Gluconeogênese/fisiologia , Resistência à Insulina/fisiologia , Histona Desmetilases com o Domínio Jumonji/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , MicroRNAs/genéticaRESUMO
Anurans undergo significant physiological changes when exposed to environmental stressors such as low temperatures and humidity. Energy metabolism and substrate management play a crucial role in their survival success. Therefore, understanding the role of the gluconeogenic pathway and demonstrating its existence in amphibians is essential. In this study, we exposed the subtropical frog Boana pulchella to cooling (-2.5°C for 24â h) and dehydration conditions (40% of body water loss), followed by recovery (24â h), and assessed gluconeogenesis activity from alanine, lactate, glycerol and glutamine in the liver, muscle and kidney. We report for the first time that gluconeogenesis activity by 14C-alanine and 14C-lactate conversion to glucose occurs in the muscle tissue of frogs, and this tissue activity is influenced by environmental conditions. Against the control group, liver gluconeogenesis from 14C-lactate and 14C-glycerol was lower during cooling and recovery (P<0.01), and gluconeogenesis from 14C-glutamine in the kidneys was also lower during cooling (P<0.05). In dehydration exposure, gluconeogenesis from 14C-lactate in the liver was lower during recovery, and that from 14C-alanine in the muscle was lower during dehydration (P<0.05). Moreover, we observed that gluconeogenesis activity and substrate preference respond differently to cold and dehydration. These findings highlight tissue-specific plasticity dependent on the nature of the encountered stressor, offering valuable insights for future studies exploring this plasticity, elucidating the importance of the gluconeogenic pathway and characterizing it in anuran physiology.
Assuntos
Anuros , Temperatura Baixa , Desidratação , Gluconeogênese , Animais , Gluconeogênese/fisiologia , Anuros/fisiologia , Anuros/metabolismo , Desidratação/fisiopatologia , Fígado/metabolismo , Rim/metabolismo , Rim/fisiologia , Músculos/metabolismo , Músculos/fisiologia , MasculinoRESUMO
The beneficial effects of high-fat low-carbohydrate (HFLC) diets on glucose metabolism have been questioned and their effects on liver metabolism are not totally clear. The aim of this work was to investigate the effects of an HFLC diet under different energy conditions on glucose homeostasis, fatty liver development, and hepatic gluconeogenesis using the isolated perfused rat liver. HFLC diet (79% fat, 19% protein, and 2% carbohydrates in Kcal%) was administered to rats for 4 weeks under three conditions: ad libitum (hypercaloric), isocaloric, and hypocaloric (energy reduction of 20%). Fasting blood glucose levels and total fat in the liver were higher in all HFLC diet rats. Oral glucose tolerance was impaired in isocaloric and hypercaloric groups, although insulin sensitivity was not altered. HFLC diet also caused marked liver metabolic alterations: higher gluconeogenesis rate from lactate and a reduced capacity to metabolize alanine, the latter effect being more intense in the hypocaloric condition. Thus, even when HFLC diets are used for weight loss, our data imply that they can potentially cause harmful consequences for the liver.
Assuntos
Gorduras na Dieta , Fígado Gorduroso , Ratos , Animais , Gluconeogênese , Carboidratos da Dieta/efeitos adversos , Dieta com Restrição de Carboidratos , Fígado/metabolismo , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/metabolismo , Glicemia/metabolismo , Homeostase , Glucose/metabolismoRESUMO
The prevalence of hypothyroidism in patients with nonalcoholic fatty liver disease (NAFLD) is high (22.4%). Thyroid hormones (THs) regulate many metabolic activities in the liver by promoting the export and oxidation of lipids, as well as de novo lipogenesis. They also control hepatic insulin sensitivity and suppress hepatic gluconeogenesis. Because of its importance in lipid and carbohydrate metabolism, the involvement of thyroid dysfunction in the pathogenesis of NAFLD seems plausible. The mechanisms implicated in this relationship include high thyroid-stimulating hormone (TSH) levels, low TH levels, and chronic inflammation. The activity of the TH receptor (THR)-ß in response to THs is essential in the pathogenesis of hypothyroidism-induced NAFLD. Therefore, an orally active selective liver THR-ß agonist, Resmetirom (MGL-3196), was developed, and has been shown to reduce liver fat content, and as a secondary end point, to improve nonalcoholic steatohepatitis. The treatment of NAFLD with THR-ß agonists seems quite promising, and other agonists are currently under development and investigation. This review aims to shine a light on the pathophysiological and epidemiological evidence regarding this relationship and the effect that treatment with THs and selective liver THR-ß agonists have on hepatic lipid metabolism.
Assuntos
Hipotireoidismo , Hepatopatia Gordurosa não Alcoólica , Doenças da Glândula Tireoide , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fígado/metabolismo , Doenças da Glândula Tireoide/patologia , Hormônios Tireóideos/metabolismo , Hipotireoidismo/complicações , GluconeogêneseRESUMO
Occurrence of hyperglycemia upon infection is associated with worse clinical outcome in COVID-19 patients. However, it is still unknown whether SARS-CoV-2 directly triggers hyperglycemia. Herein, we interrogated whether and how SARS-CoV-2 causes hyperglycemia by infecting hepatocytes and increasing glucose production. We performed a retrospective cohort study including patients that were admitted at a hospital with suspicion of COVID-19. Clinical and laboratory data were collected from the chart records and daily blood glucose values were analyzed to test the hypothesis on whether COVID-19 was independently associated with hyperglycemia. Blood glucose was collected from a subgroup of nondiabetic patients to assess pancreatic hormones. Postmortem liver biopsies were collected to assess the presence of SARS-CoV-2 and its transporters in hepatocytes. In human hepatocytes, we studied the mechanistic bases of SARS-CoV-2 entrance and its gluconeogenic effect. SARS-CoV-2 infection was independently associated with hyperglycemia, regardless of diabetic history and beta cell function. We detected replicating viruses in human hepatocytes from postmortem liver biopsies and in primary hepatocytes. We found that SARS-CoV-2 variants infected human hepatocytes in vitro with different susceptibility. SARS-CoV-2 infection in hepatocytes yields the release of new infectious viral particles, though not causing cell damage. We showed that infected hepatocytes increase glucose production and this is associated with induction of PEPCK activity. Furthermore, our results demonstrate that SARS-CoV-2 entry in hepatocytes occurs partially through ACE2- and GRP78-dependent mechanisms. SARS-CoV-2 infects and replicates in hepatocytes and exerts a PEPCK-dependent gluconeogenic effect in these cells that potentially is a key cause of hyperglycemia in infected patients.
Assuntos
COVID-19 , Hiperglicemia , Humanos , COVID-19/complicações , SARS-CoV-2 , Gluconeogênese , Glicemia , Estudos Retrospectivos , Hepatócitos , Hiperglicemia/complicações , GlucoseRESUMO
Interleukin 6 (IL6) is an multifunctional cytokine that modulates several biological responses, including glucose metabolism. However, its acute effects on hepatic glucose release are still uncertain. The main purpose of this study was to investigate the effects of IL6 on gluconeogenesis from several glucose precursors (alanine, pyruvate and glutamine) and on the suppressive action of insulin on cAMP-stimulated glycogen catabolism in rat liver. IL6 effect on insulin peripheral sensitivity was also evaluated. IL6 was injected intravenously into rats and, 1 h later, gluconeogenesis and glycogenolysis were assessed in liver perfusion and peripheral insulin sensitivity by insulin tolerance test (ITT). IL6 intravenous injection increased hepatic glucose production from alanine, without changing pyruvate, lactate and urea production. IL6 injection also increased hepatic glucose production from pyruvate and glutamine. In addition, IL6 decreased the suppressive effect of insulin on cAMP-stimulated glucose and lactate production and glycogenolysis, without affecting pyruvate production. Furthermore, IL6 reduced the plasma glucose disappearance constant (kITT), an indicator of insulin resistance. In conclusion, IL6 acutely increased hepatic glucose release (gluconeogenesis and glycogenolysis) by a mechanism that likely involved the induction of insulin resistance in the liver, as evidenced by the reduced suppressive effect of insulin on cAMP-stimulated glycogen catabolism. In consistency, IL6 acutely induced peripheral insulin resistance.
Assuntos
Glicogenólise , Resistência à Insulina , Ratos , Animais , Gluconeogênese , Insulina/farmacologia , Insulina/metabolismo , Interleucina-6/metabolismo , Glutamina/metabolismo , Glutamina/farmacologia , Glucose/farmacologia , Glucose/metabolismo , Glicogênio/metabolismo , Glicogênio/farmacologia , Fígado/metabolismo , Ácido Láctico/farmacologia , Ácido Láctico/metabolismo , Piruvatos/metabolismo , Piruvatos/farmacologia , Alanina/farmacologia , Alanina/metabolismo , GlicemiaRESUMO
Trichophyton rubrum is the primary causative agent of dermatophytosis worldwide. This fungus colonizes keratinized tissues and uses keratin as a nutritional source during infection. In T. rubrum-host interactions, sensing a hostile environment triggers the adaptation of its metabolic machinery to ensure its survival. The glyoxylate cycle has emerged as an alternative metabolic pathway when glucose availability is limited; this enables the conversion of simple carbon compounds into glucose via gluconeogenesis. In this study, we investigated the impact of stuA deletion on the response of glyoxylate cycle enzymes during fungal growth under varying culture conditions in conjunction with post-transcriptional regulation through alternative splicing of the genes encoding these enzymes. We revealed that the ΔstuA mutant downregulated the malate synthase and isocitrate lyase genes in a keratin-containing medium or when co-cultured with human keratinocytes. Alternative splicing of an isocitrate lyase gene yielded a new isoform. Enzymatic activity assays showed specific instances where isocitrate lyase and malate synthase activities were affected in the mutant strain compared to the wild type strain. Taken together, our results indicate a relevant balance in transcriptional regulation that has distinct effects on the enzymatic activities of malate synthase and isocitrate lyase.
Assuntos
Arthrodermataceae , Fatores de Transcrição , Humanos , Isocitrato Liase/genética , Malato Sintase/genética , Gluconeogênese/genética , Processamento Alternativo , Carbono , Glucose , Queratinas , GlioxilatosRESUMO
AIMS: to investigate the effects of resveratrol on glycogen catabolism and gluconeogenesis in perfused livers of healthy and arthritic rats. The actions of resveratrol-3-O-glucuronide (R3G) and the biotransformation of resveratrol into R3G was further evaluated in the livers. MAIN METHODS: arthritis was induced with Freund's adjuvant. Resveratrol at concentrations of 10, 25, 50, 100 and 200 µM and 200 µM R3G were introduced in perfused livers. Resveratrol and metabolites were measured in the outflowing perfusate. Respiration of isolated mitochondria and activity of gluconeogenic enzymes were also evaluated in the livers. KEY FINDINGS: resveratrol inhibited glycogen catabolism when infused at concentrations above 50 µM and gluconeogenesis even at 10 µM in both healthy and arthritic rat livers, but more sensitive in these latter. Resveratrol above 100 µM inhibited ADP-stimulated respiration and the activities of NADH- and succinate-oxidases in mitochondria, which were partially responsible for gluconeogenesis inhibition. Pyruvate carboxylase activity was inhibited by 25 µM resveratrol and should inhibit gluconeogenesis already at low concentrations. Resveratrol was significantly metabolized to R3G in healthy rat livers, however, R3G formation was lower in arthritic rat livers. The latter must be in part a consequence of a lower glucose disposal for glucuronidation. When compared to resveratrol, R3G inhibited gluconeogenesis in a lower extension and glycogen catabolism in a higher extension. SIGNIFICANCE: the effects of resveratrol and R3G tended to be transitory and existed only when the resveratrol is present in the organ, however, they should be considered because significant serum concentrations of both are found after oral ingestion of resveratrol.