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1.
Cell ; 185(18): 3441-3456.e19, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-36055202

RESUMO

Great progress has been made in understanding gut microbiomes' products and their effects on health and disease. Less attention, however, has been given to the inputs that gut bacteria consume. Here, we quantitatively examine inputs and outputs of the mouse gut microbiome, using isotope tracing. The main input to microbial carbohydrate fermentation is dietary fiber and to branched-chain fatty acids and aromatic metabolites is dietary protein. In addition, circulating host lactate, 3-hydroxybutyrate, and urea (but not glucose or amino acids) feed the gut microbiome. To determine the nutrient preferences across bacteria, we traced into genus-specific bacterial protein sequences. We found systematic differences in nutrient use: most genera in the phylum Firmicutes prefer dietary protein, Bacteroides dietary fiber, and Akkermansia circulating host lactate. Such preferences correlate with microbiome composition changes in response to dietary modifications. Thus, diet shapes the microbiome by promoting the growth of bacteria that preferentially use the ingested nutrients.


Assuntos
Microbioma Gastrointestinal , Animais , Bactérias , Dieta , Fibras na Dieta/metabolismo , Proteínas Alimentares/metabolismo , Lactatos/metabolismo , Camundongos , Nutrientes
2.
Nature ; 579(7800): 586-591, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32214246

RESUMO

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


Assuntos
Acetatos/metabolismo , Açúcares da Dieta/metabolismo , Frutose/metabolismo , Microbioma Gastrointestinal/fisiologia , Lipogênese , Fígado/metabolismo , ATP Citrato (pro-S)-Liase/deficiência , ATP Citrato (pro-S)-Liase/genética , ATP Citrato (pro-S)-Liase/metabolismo , Acetato-CoA Ligase/deficiência , Acetato-CoA Ligase/genética , Acetato-CoA Ligase/metabolismo , Acetilcoenzima A/metabolismo , Animais , Ácido Cítrico/metabolismo , Açúcares da Dieta/administração & dosagem , Açúcares da Dieta/farmacologia , Ácidos Graxos/metabolismo , Frutose/administração & dosagem , Frutose/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Marcação por Isótopo , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Camundongos , Especificidade por Substrato
3.
Nat Methods ; 19(2): 223-230, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35132243

RESUMO

Isotope tracing has helped to determine the metabolic activities of organs. Methods to probe metabolic heterogeneity within organs are less developed. We couple stable-isotope-labeled nutrient infusion to matrix-assisted laser desorption ionization imaging mass spectrometry (iso-imaging) to quantitate metabolic activity in mammalian tissues in a spatially resolved manner. In the kidney, we visualize gluconeogenic flux and glycolytic flux in the cortex and medulla, respectively. Tricarboxylic acid cycle substrate usage differs across kidney regions; glutamine and citrate are used preferentially in the cortex and fatty acids are used in the medulla. In the brain, we observe spatial gradations in carbon inputs to the tricarboxylic acid cycle and glutamate under a ketogenic diet. In a carbohydrate-rich diet, glucose predominates throughout but in a ketogenic diet, 3-hydroxybutyrate contributes most strongly in the hippocampus and least in the midbrain. Brain nitrogen sources also vary spatially; branched-chain amino acids contribute most in the midbrain, whereas ammonia contributes in the thalamus. Thus, iso-imaging can reveal the spatial organization of metabolic activity.


Assuntos
Encéfalo/metabolismo , Isótopos de Carbono/farmacocinética , Rim/metabolismo , Isótopos de Nitrogênio/farmacocinética , Animais , Dieta , Enzimas , Gluconeogênese , Ácido Glutâmico/biossíntese , Glicólise , Masculino , Camundongos Endogâmicos C57BL , Imagem Molecular , Análise de Célula Única , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Espectrometria de Massas em Tandem , Ácidos Tricarboxílicos/metabolismo , Fluxo de Trabalho
4.
Nat Methods ; 18(11): 1377-1385, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34711973

RESUMO

Liquid chromatography-high-resolution mass spectrometry (LC-MS)-based metabolomics aims to identify and quantify all metabolites, but most LC-MS peaks remain unidentified. Here we present a global network optimization approach, NetID, to annotate untargeted LC-MS metabolomics data. The approach aims to generate, for all experimentally observed ion peaks, annotations that match the measured masses, retention times and (when available) tandem mass spectrometry fragmentation patterns. Peaks are connected based on mass differences reflecting adduction, fragmentation, isotopes, or feasible biochemical transformations. Global optimization generates a single network linking most observed ion peaks, enhances peak assignment accuracy, and produces chemically informative peak-peak relationships, including for peaks lacking tandem mass spectrometry spectra. Applying this approach to yeast and mouse data, we identified five previously unrecognized metabolites (thiamine derivatives and N-glucosyl-taurine). Isotope tracer studies indicate active flux through these metabolites. Thus, NetID applies existing metabolomic knowledge and global optimization to substantially improve annotation coverage and accuracy in untargeted metabolomics datasets, facilitating metabolite discovery.


Assuntos
Algoritmos , Curadoria de Dados/normas , Fígado/metabolismo , Metaboloma , Metabolômica/normas , Saccharomyces cerevisiae/metabolismo , Animais , Cromatografia Líquida/métodos , Curadoria de Dados/métodos , Metabolômica/métodos , Camundongos , Espectrometria de Massas em Tandem/métodos
5.
Biochemistry ; 56(15): 2076-2085, 2017 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-28353343

RESUMO

Membrane proteins play vital roles in cell signaling, molecular transportation, and cell adhesion. The interactions of transmembrane domains are much less well understood than those of their water-soluble counterparts, and they have been deemed "undruggable" despite their important biological functions such as protein anchoring, signal transduction, and ligand recognition. Nevertheless, continual developments in this area have revealed useful probes for investigating and regulating these membrane proteins. This review summarizes and evaluates the strategies available for discovering small molecules and peptides that recognize the protein transmembrane domains of membrane proteins, with a particular focus on rational design and library screening.


Assuntos
Proteínas de Membrana/metabolismo , Peptídeos/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Humanos , Masculino , Ligação Proteica
6.
J Hum Genet ; 60(3): 157-60, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25566755

RESUMO

A young Chinese male patient was identified as homozygous for Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3. This patient had a 4-year medical history mainly presenting severe ataxia, abnormal eye movement and pyramidal signs. Magnetic resonance imaging of the brain and cervical spinal cord revealed no obvious abnormality despite the severe symptoms and the findings of an electromyogram. However, brainstem auditory evoked potential indicated peripheral impairment and visual evoked potential indicated central impairment of his visual pathways. Molecular diagnosis revealed the pattern of CAG repeat units of this patient was 71/71. This case demonstrates that homozygosity for MJD enhances the clinical severity of the disease, which suggests that genetic education is of great importance.


Assuntos
Ataxina-3/genética , Doença de Machado-Joseph/genética , Proteínas Repressoras/genética , Repetições de Trinucleotídeos/genética , Povo Asiático/genética , Tronco Encefálico/metabolismo , Tronco Encefálico/fisiopatologia , China , Consanguinidade , Análise Mutacional de DNA , Eletromiografia , Potenciais Evocados Auditivos/genética , Potenciais Evocados Auditivos/fisiologia , Potenciais Evocados Visuais/genética , Potenciais Evocados Visuais/fisiologia , Saúde da Família , Feminino , Homozigoto , Humanos , Doença de Machado-Joseph/patologia , Doença de Machado-Joseph/fisiopatologia , Masculino , Pessoa de Meia-Idade , Linhagem , Adulto Jovem
7.
RSC Adv ; 14(23): 16411-16420, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38774619

RESUMO

In this work, an attapulgite-graphene nanocomposite was prepared. The tribological properties of the prepared attapulgite-graphene nanocomposite as an additive for 200SN mineral lubricating oil were investigated using an SRV-IV tribometer through ball-on-disk contact mode for the first time. The characterization of the prepared nanocomposite indicated that attapulgite nanofibers are enveloped by the graphene nanosheets and present fine combination. The tribological test results show that the friction-reducing and antiwear properties of 200SN were obviously improved by adding the attapulgite-graphene nanocomposite. Through the characterization and analysis of the worn surface and cross-section, it was found that a tribofilm composed of Fe, Fe3O4, FeO, Fe2O3, FeOOH, graphite, graphene, SiO2 and organic compounds was formed on the worn surface. Furthermore, the bonding between the tribofilm and steel matrix is tight. The tribofilm and lubricating oil achieve a solid-liquid coupling lubrication effect, which is responsible for the improvement of the friction-reducing and antiwear properties.

8.
bioRxiv ; 2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38562797

RESUMO

Taurine is a conditionally essential micronutrient and one of the most abundant amino acids in humans1-3. In endogenous taurine metabolism, dedicated enzymes are involved in biosynthesis of taurine from cysteine as well as the downstream derivatization of taurine into secondary taurine metabolites4,5. One such taurine metabolite is N-acetyltaurine6. Levels of N-acetyltaurine are dynamically regulated by diverse physiologic perturbations that alter taurine and/or acetate flux, including endurance exercise7, nutritional taurine supplementation8, and alcohol consumption6,9. While taurine N-acetyltransferase activity has been previously detected in mammalian cells6,7, the molecular identity of this enzyme, and the physiologic relevance of N-acetyltaurine, have remained unknown. Here we show that the orphan body mass index-associated enzyme PTER (phosphotriesterase-related)10 is the principal mammalian taurine N-acetyltransferase/hydrolase. In vitro, recombinant PTER catalyzes bidirectional taurine N-acetylation with free acetate as well as the reverse N-acetyltaurine hydrolysis reaction. Genetic ablation of PTER in mice results in complete loss of tissue taurine N-acetyltransferase/hydrolysis activities and systemic elevation of N-acetyltaurine levels. Upon stimuli that increase taurine levels, PTER-KO mice exhibit lower body weight, reduced adiposity, and improved glucose homeostasis. These phenotypes are recapitulated by administration of N-acetyltaurine to wild-type mice. Lastly, the anorexigenic and anti-obesity effects of N-acetyltaurine require functional GFRAL receptors. Together, these data uncover enzymatic control of a previously enigmatic pathway of secondary taurine metabolism linked to energy balance.

9.
Cell Metab ; 35(11): 2077-2092.e6, 2023 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-37802078

RESUMO

Cold-induced thermogenesis (CIT) is widely studied as a potential avenue to treat obesity, but a thorough understanding of the metabolic changes driving CIT is lacking. Here, we present a comprehensive and quantitative analysis of the metabolic response to acute cold exposure, leveraging metabolomic profiling and minimally perturbative isotope tracing studies in unanesthetized mice. During cold exposure, brown adipose tissue (BAT) primarily fueled the tricarboxylic acid (TCA) cycle with fat in fasted mice and glucose in fed mice, underscoring BAT's metabolic flexibility. BAT minimally used branched-chain amino acids or ketones, which were instead avidly consumed by muscle during cold exposure. Surprisingly, isotopic labeling analyses revealed that BAT uses glucose largely for TCA anaplerosis via pyruvate carboxylation. Finally, we find that cold-induced hepatic gluconeogenesis is critical for CIT during fasting, demonstrating a key functional role for glucose metabolism. Together, these findings provide a detailed map of the metabolic rewiring driving acute CIT.


Assuntos
Resposta ao Choque Frio , Termogênese , Animais , Camundongos , Termogênese/fisiologia , Tecido Adiposo Marrom/metabolismo , Glucose/metabolismo , Metabolismo Energético , Temperatura Baixa
10.
J Air Waste Manag Assoc ; 72(8): 815-827, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35113006

RESUMO

Emission inspection of motor vehicles (emission inspection) is a crucial player in solving the problem of motor vehicle exhaust pollution, and research on the features affecting emission inspection results and their importance is a basis for optimizing the environmental management of motor vehicles. However, there is no study on the multi-feature impact analysis of the emission inspection results. This hinders the emission inspection from playing a better guiding role in the policy formulation of motor vehicle management. In this paper, the ensemble learning algorithm and interpretable machine learning theory are used. Nineteen feature indicators and over 400,000 vehicle mass analysis system (VMAS) detection data in Chengdu were selected from the emission inspection database to construct prediction models for emission inspection results. Moreover, the factors affecting emission inspection results and their ranks by importance were also obtained. The results revealed that the environment has a strong influence on the outcomes from emission inspections (accounting for about one-third of the total effect). Besides, the following eight feature indicators displayed great effects on emission inspection results in sequence: emission inspection agency (18.38%), world manufacturer code (15.01%), vehicle usage days (9.60%), transmission type (9.41%), accumulated mileage (9.21%), emission standard (5.82%), temperature (5.54%), and driving mode (5.50%). In this study, prediction models for emission inspection results are established, and the results are interpreted based on the interpretable machine learning theory. It is considered that more attention should be paid to the effect of inspection differences among emission inspection agencies on fairness, as well as the effects of differences in world manufacturer and transmission type on vehicle deterioration in future research. The supervision of emission inspection agencies, training of inspectors, elimination of obsolete vehicles, and government-guided purchase should be strengthened. This study provides empirical support for optimizing the formulation of motor vehicle environmental management policies.Implications: Emission inspection of motor vehicles (emission inspection) is a crucial player in solving the problem of motor vehicle exhaust pollution. In this work, prediction models for emission of motor vehicles inspection results are established. The results revealed that following eight feature indicators displayed great effects on emission inspection results in sequence: emission inspection agency (18.38%), world manufacturer code (15.01%), vehicle usage days (9.60%), transmission type (9.41%), accumulated mileage (9.21%), emission standard (5.82%), temperature (5.54%), and driving mode (5.50%). It is considered that more attention should be paid to the effect of inspection differences among emission inspection agencies on fairness, as well as the effects of differences in world manufacturer and transmission type on vehicle deterioration in future research. The supervision of emission inspection agencies, training of inspectors, elimination of obsolete vehicles, and government-guided purchase should be strengthened. This study provides empirical support for optimizing the formulation of motor vehicle environmental management policies.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Poluição do Ar/prevenção & controle , Monitoramento Ambiental/métodos , Aprendizado de Máquina , Veículos Automotores , Emissões de Veículos/análise
11.
Nat Metab ; 4(1): 141-152, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35058631

RESUMO

Homeostasis maintains serum metabolites within physiological ranges. For glucose, this requires insulin, which suppresses glucose production while accelerating its consumption. For other circulating metabolites, a comparable master regulator has yet to be discovered. Here we show that, in mice, many circulating metabolites are cleared via the tricarboxylic acid cycle (TCA) cycle in linear proportionality to their circulating concentration. Abundant circulating metabolites (essential amino acids, serine, alanine, citrate, 3-hydroxybutyrate) were administered intravenously in perturbative amounts and their fluxes were measured using isotope labelling. The increased circulating concentrations induced by the perturbative infusions hardly altered production fluxes while linearly enhancing consumption fluxes and TCA contributions. The same mass action relationship between concentration and consumption flux largely held across feeding, fasting and high- and low-protein diets, with amino acid homeostasis during fasting further supported by enhanced endogenous protein catabolism. Thus, despite the copious regulatory machinery in mammals, circulating metabolite homeostasis is achieved substantially through mass action-driven oxidation.


Assuntos
Biomarcadores/sangue , Homeostase , Metaboloma , Algoritmos , Aminoácidos/metabolismo , Animais , Ciclo do Ácido Cítrico , Metabolismo Energético , Glucose/metabolismo , Masculino , Metabolômica/métodos , Camundongos , Camundongos Knockout , Modelos Biológicos , Oxirredução
12.
Med ; 3(2): 119-136, 2022 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-35425930

RESUMO

Background: Ketogenic diet is a potential means of augmenting cancer therapy. Here, we explore ketone body metabolism and its interplay with chemotherapy in pancreatic cancer. Methods: Metabolism and therapeutic responses of murine pancreatic cancer were studied using KPC primary tumors and tumor chunk allografts. Mice on standard high-carbohydrate diet or ketogenic diet were treated with cytotoxic chemotherapy (nab-paclitaxel, gemcitabine, cisplatin). Metabolic activity was monitored with metabolomics and isotope tracing, including 2H- and 13C-tracers, liquid chromatography-mass spectrometry, and imaging mass spectrometry. Findings: Ketone bodies are unidirectionally oxidized to make NADH. This stands in contrast to the carbohydrate-derived carboxylic acids lactate and pyruvate, which rapidly interconvert, buffering NADH/NAD. In murine pancreatic tumors, ketogenic diet decreases glucose's concentration and tricarboxylic acid cycle contribution, enhances 3-hydroxybutyrate's concentration and tricarboxylic acid contribution, and modestly elevates NADH, but does not impact tumor growth. In contrast, the combination of ketogenic diet and cytotoxic chemotherapy substantially raises tumor NADH and synergistically suppresses tumor growth, tripling the survival benefits of chemotherapy alone. Chemotherapy and ketogenic diet also synergize in immune-deficient mice, although long-term growth suppression was only observed in mice with an intact immune system. Conclusions: Ketogenic diet sensitizes murine pancreatic cancer tumors to cytotoxic chemotherapy. Based on these data, we have initiated a randomized clinical trial of chemotherapy with standard versus ketogenic diet for patients with metastatic pancreatic cancer (NCT04631445).


Assuntos
Dieta Cetogênica , Neoplasias Pancreáticas , Animais , Carboidratos , Dieta Cetogênica/métodos , Humanos , Camundongos , NAD , Neoplasias Pancreáticas/dietoterapia , Neoplasias Pancreáticas/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Pancreáticas
13.
Cell Metab ; 34(12): 1947-1959.e5, 2022 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-36476934

RESUMO

Nicotinamide adenine dinucleotide (NAD) is an essential redox cofactor in mammals and microbes. Here we use isotope tracing to investigate the precursors supporting NAD synthesis in the gut microbiome of mice. We find that dietary NAD precursors are absorbed in the proximal part of the gastrointestinal tract and not available to microbes in the distal gut. Instead, circulating host nicotinamide enters the gut lumen and supports microbial NAD synthesis. The microbiome converts host-derived nicotinamide into nicotinic acid, which is used for NAD synthesis in host tissues and maintains circulating nicotinic acid levels even in the absence of dietary consumption. Moreover, the main route from oral nicotinamide riboside, a widely used nutraceutical, to host NAD is via conversion into nicotinic acid by the gut microbiome. Thus, we establish the capacity for circulating host micronutrients to feed the gut microbiome, and in turn be transformed in a manner that enhances host metabolic flexibility.


Assuntos
NAD , Niacina , Camundongos , Animais , Niacinamida/farmacologia , Mamíferos
14.
Nat Metab ; 3(12): 1608-1620, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34845393

RESUMO

Carbohydrate can be converted into fat by de novo lipogenesis, a process upregulated in fatty liver disease. Chemically, de novo lipogenesis involves polymerization and reduction of acetyl-CoA, using NADPH as the electron donor. The feedstocks used to generate acetyl-CoA and NADPH in lipogenic tissues remain, however, unclear. Here we show using stable isotope tracing in mice that de novo lipogenesis in adipose is supported by glucose and its catabolism via the pentose phosphate pathway to make NADPH. The liver, in contrast, derives acetyl-CoA for lipogenesis from acetate and lactate, and NADPH from folate-mediated serine catabolism. Such NADPH generation involves the cytosolic serine pathway in liver running in the opposite direction to that observed in most tissues and tumours, with NADPH made by the SHMT1-MTHFD1-ALDH1L1 reaction sequence. SHMT inhibition decreases hepatic lipogenesis. Thus, liver folate metabolism is distinctively wired to support cytosolic NADPH production and lipogenesis. More generally, while the same enzymes are involved in fat synthesis in liver and adipose, different substrates are used, opening the door to tissue-specific pharmacological interventions.


Assuntos
Lipogênese , Fígado/metabolismo , NADP/metabolismo , Serina/metabolismo , Acetilcoenzima A/metabolismo , Tecido Adiposo/metabolismo , Aminoidrolases/metabolismo , Animais , Ácidos Graxos/metabolismo , Feminino , Ácido Fólico/metabolismo , Formiato-Tetra-Hidrofolato Ligase/metabolismo , Glutamina/metabolismo , Glicina Hidroximetiltransferase/metabolismo , Hepatócitos/metabolismo , Metabolismo dos Lipídeos , Masculino , Redes e Vias Metabólicas , Metilenotetra-Hidrofolato Desidrogenase (NADP)/metabolismo , Camundongos , Complexos Multienzimáticos/metabolismo , Fosforilação Oxidativa , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/metabolismo
15.
Nat Metab ; 2(7): 586-593, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32694791

RESUMO

Per capita fructose consumption has increased 100-fold over the last century1. Epidemiological studies suggest that excessive fructose consumption, and especially consumption of sweet drinks, is associated with hyperlipidaemia, non-alcoholic fatty liver disease, obesity and diabetes2-7. Fructose metabolism begins with its phosphorylation by the enzyme ketohexokinase (KHK), which exists in two alternatively spliced forms8. The more active isozyme, KHK-C, is expressed most strongly in the liver, but also substantially in the small intestine9,10 where it drives dietary fructose absorption and conversion into other metabolites before fructose reaches the liver11-13. It is unclear whether intestinal fructose metabolism prevents or contributes to fructose-induced lipogenesis and liver pathology. Here we show that intestinal fructose catabolism mitigates fructose-induced hepatic lipogenesis. In mice, intestine-specific KHK-C deletion increases dietary fructose transit to the liver and gut microbiota and sensitizes mice to fructose's hyperlipidaemic effects and hepatic steatosis. In contrast, intestine-specific KHK-C overexpression promotes intestinal fructose clearance and decreases fructose-induced lipogenesis. Thus, intestinal fructose clearance capacity controls the rate at which fructose can be safely ingested. Consistent with this, we show that the same amount of fructose is more strongly lipogenic when drunk than eaten, or when administered as a single gavage, as opposed to multiple doses spread over 45 min. Collectively, these data demonstrate that fructose induces lipogenesis when its dietary intake rate exceeds the intestinal clearance capacity. In the modern context of ready food availability, the resulting fructose spillover drives metabolic syndrome. Slower fructose intake, tailored to intestinal capacity, can mitigate these consequences.


Assuntos
Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/metabolismo , Frutose , Intestino Delgado/metabolismo , Acetilcoenzima A/metabolismo , Administração Oral , Animais , Dieta , Ácidos Graxos não Esterificados/metabolismo , Frutoquinases/genética , Frutoquinases/metabolismo , Frutose/administração & dosagem , Frutose/metabolismo , Microbioma Gastrointestinal , Humanos , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/metabolismo , Lipogênese , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos
16.
Cell Metab ; 32(4): 676-688.e4, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32791100

RESUMO

Mammalian organs are nourished by nutrients carried by the blood circulation. These nutrients originate from diet and internal stores, and can undergo various interconversions before their eventual use as tissue fuel. Here we develop isotope tracing, mass spectrometry, and mathematical analysis methods to determine the direct sources of circulating nutrients, their interconversion rates, and eventual tissue-specific contributions to TCA cycle metabolism. Experiments with fifteen nutrient tracers enabled extensive accounting for both circulatory metabolic cycles and tissue TCA inputs, across fed and fasted mice on either high-carbohydrate or ketogenic diet. We find that a majority of circulating carbon flux is carried by two major cycles: glucose-lactate and triglyceride-glycerol-fatty acid. Futile cycling through these pathways is prominent when dietary content of the associated nutrients is low, rendering internal metabolic activity robust to food choice. The presented in vivo flux quantification methods are broadly applicable to different physiological and disease states.


Assuntos
Ácidos Graxos/metabolismo , Glucose/metabolismo , Glicerol/metabolismo , Ácido Láctico/metabolismo , Triglicerídeos/metabolismo , Animais , Ciclo do Ácido Cítrico , Camundongos , Camundongos Endogâmicos C57BL
17.
Sci Adv ; 5(7): eaav1564, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31355328

RESUMO

Endosomal Toll-like receptors (TLRs) mediate intracellular innate immunity via the recognition of DNA and RNA sequences. Recent work has reported a role for extracellular vesicles (EVs), known to transfer various nucleic acids, in uptake of TLR-activating molecules, raising speculation about possible roles of EVs in innate immune surveillance. Whether EV-mediated uptake is a general mechanism, however, was unresolved; and the molecular machinery that might be involved was unknown. We show that, when macrophages are stimulated with the TLR9 agonist CpG oligodeoxynucleotides (ODN), the secreted EVs transport ODN into naïve macrophages and induce the release of chemokine TNF-α. In addition, these EVs transfer Cdc42 into recipient cells, resulting in further enhancement of their cellular uptake. Transport of ODN and Cdc42 from TLR9-activated macrophages to naïve cells via EVs exerts synergetic effects in propagation of the intracellular immune response, suggesting a general mechanism of EV-mediated uptake of pathogen-associated molecular patterns.


Assuntos
Vesículas Extracelulares/genética , Receptor Toll-Like 9/genética , Fator de Necrose Tumoral alfa/genética , Proteína cdc42 de Ligação ao GTP/genética , Linhagem Celular , DNA/genética , Endossomos/genética , Endossomos/imunologia , Vesículas Extracelulares/imunologia , Regulação da Expressão Gênica/genética , Humanos , Imunidade Celular , Macrófagos/imunologia , Nanopartículas/química , Oligodesoxirribonucleotídeos/genética , Proteômica , RNA/genética , Proteína cdc42 de Ligação ao GTP/imunologia
18.
Int J Clin Exp Pathol ; 12(6): 2275-2278, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31934051

RESUMO

INTRODUCTION: Congenital Self-Healing Langerhans Cell Histiocytosis (CSHLCH) is rare, characterized by cutaneous lesions at birth or in the neonatal period, and absence of systemic lesions. MATERIALS AND METHODS: Skin biopsy was performed and the histologic examination of the skin section, routinely stained with hematoxylin-eosin. Paraffin sections were stained by immunohistochemical study which were carried out according to the manufacturer's protocols. RESULT: Seven cases of CSHLCH were recruited. 28.6% (2/7) of the cutaneous lesions were multiple, 71.4% (5/7) were solitary. Skin biopsy was performed and the histologic examination of the skin section, routinely stained with hematoxylin-eosin. Microscopically, in the dermis, a dense infiltrate of histiocytic cells mixed with numerous eosinophils. These histiocytes were immunohistochemically positive for CD1a and S-100. All of the cutaneous lesions regress spontaneously, and lack of systemic involvement, the final diagnosis of Congenital Self-Healing Langerhans Cell Histiocytosis were made. No recurrence had been observed. CONCLUSION: The cutaneous lesions of CSHLCH may regress spontaneously. Spontaneous resolution of cutaneous lesions and lack of systemic involvement are essential for the diagnosis of CSHLCH. It needs long-term follow-up.

19.
Cell Metab ; 30(3): 594-606.e3, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31257152

RESUMO

Mammalian organs continually exchange metabolites via circulation, but systems-level analysis of this shuttling process is lacking. Here, we compared, in fasted pigs, metabolite concentrations in arterial blood versus draining venous blood from 11 organs. Greater than 90% of metabolites showed arterial-venous differences across at least one organ. Surprisingly, the liver and kidneys released not only glucose but also amino acids, both of which were consumed primarily by the intestine and pancreas. The liver and kidneys exhibited additional unexpected activities: liver preferentially burned unsaturated over more atherogenic saturated fatty acids, whereas the kidneys were unique in burning circulating citrate and net oxidizing lactate to pyruvate, thereby contributing to circulating redox homeostasis. Furthermore, we observed more than 700 other cases of tissue-specific metabolite production or consumption, such as release of nucleotides by the spleen and TCA intermediates by pancreas. These data constitute a high-value resource, providing a quantitative atlas of inter-organ metabolite exchange.


Assuntos
Rim/metabolismo , Fígado/metabolismo , Suínos/metabolismo , Aminoácidos/sangue , Animais , Artérias , Glicemia , Ácido Cítrico/sangue , Jejum/sangue , Ácidos Graxos/sangue , Mucosa Intestinal/irrigação sanguínea , Mucosa Intestinal/metabolismo , Rim/irrigação sanguínea , Ácido Láctico/sangue , Fígado/irrigação sanguínea , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pâncreas/irrigação sanguínea , Pâncreas/metabolismo , Ácido Pirúvico/sangue , Baço/irrigação sanguínea , Baço/metabolismo , Veias
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