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BACKGROUND AND AIMS: Colonoscopy-based surveillance to prevent colorectal cancer (CRC) causes substantial burden for patients and healthcare. Stool tests may help to reduce surveillance colonoscopies, by limiting colonoscopies to individuals at increased risk of AN. METHODS: This cross-sectional observational study included individuals aged 50-75 with surveillance indication. Before bowel preparation, participants collected samples for a multitarget stool DNA (mt-sDNA) test and two fecal immunochemical tests (FITs). Test accuracies were calculated for all surveillance indications. Only for the post-polypectomy indication, most common and associated with a relatively low CRC risk, long-term impact of stool-based surveillance was evaluated with the ASCCA model. Stool-based strategies were simulated to tune each tests' positivity threshold to obtain strategies at least as effective as colonoscopy surveillance. RESULTS: 3453 individuals had results for all stool tests and colonoscopy. 2226 had previous polypectomy, 1003 previous CRC and 224 familial risk. Areas under the receiver operating characteristic curve for AN were 0.72 (95% CI; 0.69-0.75) for the mt-sDNA test, 0.61 (95% CI; 0.58-0.64) for the FIT OC-Sensor and 0.59 (95% CI; 0.56-0.61) for the FIT FOB-Gold. Stool-based post-polypectomy surveillance strategies at least as effective as colonoscopy surveillance, reduced the number of colonoscopies by 15-41% and required 5.6-9.5 stool tests over the lifetime of a person. Mt-sDNA-based surveillance was more costly than colonoscopy surveillance, whereas FIT-based surveillance saved costs. CONCLUSIONS: This study shows that stool-based post-polypectomy surveillance strategies can be safe and cost-effective, with potential to reduce the number of colonoscopies by up to 41%.
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Prevention of hypertriglyceridemia is one of the biomedical targets in Glycogen Storage Disease type Ia (GSD Ia) patients, yet it is unclear how hypoglycemia links to plasma triglyceride (TG) levels. We analyzed whole-body TG metabolism in normoglycemic (fed) and hypoglycemic (fasted) hepatocyte-specific glucose-6-phosphatase deficient (L-G6pc-/- ) mice. De novo fatty acid synthesis contributed substantially to hepatic TG accumulation in normoglycemic L-G6pc-/- mice. In hypoglycemic conditions, enhanced adipose tissue lipolysis was the main driver of liver steatosis, supported by elevated free fatty acid concentrations in GSD Ia mice and GSD Ia patients. Plasma very-low-density lipoprotein (VLDL) levels were increased in GSD Ia patients and in normoglycemic L-G6pc-/- mice, and further elevated in hypoglycemic L-G6pc-/- mice. VLDL-TG secretion rates were doubled in normo- and hypoglycemic L-G6pc-/- mice, while VLDL-TG catabolism was selectively inhibited in hypoglycemic L-G6pc-/- mice. In conclusion, fasting-induced hypoglycemia in L-G6pc-/- mice promotes adipose tissue lipolysis and arrests VLDL catabolism. This mechanism likely contributes to aggravated liver steatosis and dyslipidemia in GSD Ia patients with poor glycemic control and may explain clinical heterogeneity in hypertriglyceridemia between GSD Ia patients.
Assuntos
Glucose/metabolismo , Doença de Depósito de Glicogênio Tipo I/complicações , Hipertrigliceridemia/etiologia , Hipoglicemia/etiologia , Lipoproteínas VLDL/metabolismo , Triglicerídeos/metabolismo , Adulto , Idoso , Animais , Modelos Animais de Doenças , Fígado Gorduroso/etiologia , Feminino , Glucose-6-Fosfatase/genética , Doença de Depósito de Glicogênio Tipo I/genética , Doença de Depósito de Glicogênio Tipo I/metabolismo , Hepatócitos/metabolismo , Humanos , Hipertrigliceridemia/prevenção & controle , Hipoglicemia/metabolismo , Metabolismo dos Lipídeos , Masculino , Camundongos , Pessoa de Meia-IdadeRESUMO
BACKGROUND AND AIMS: Glycogen storage disease (GSD) type 1a is an inborn error of metabolism caused by defective glucose-6-phosphatase catalytic subunit (G6PC) activity. Patients with GSD 1a exhibit severe hepatomegaly due to glycogen and triglyceride (TG) accumulation in the liver. We have shown that the activity of carbohydrate response element binding protein (ChREBP), a key regulator of glycolysis and de novo lipogenesis, is increased in GSD 1a. In the current study, we assessed the contribution of ChREBP to nonalcoholic fatty liver disease (NAFLD) development in a mouse model for hepatic GSD 1a. APPROACH AND RESULTS: Liver-specific G6pc-knockout (L-G6pc-/- ) mice were treated with adeno-associated viruses (AAVs) 2 or 8 directed against short hairpin ChREBP to normalize hepatic ChREBP activity to levels observed in wild-type mice receiving AAV8-scrambled short hairpin RNA (shSCR). Hepatic ChREBP knockdown markedly increased liver weight and hepatocyte size in L-G6pc-/- mice. This was associated with hepatic accumulation of G6P, glycogen, and lipids, whereas the expression of glycolytic and lipogenic genes was reduced. Enzyme activities, flux measurements, hepatic metabolite analysis and very low density lipoprotein (VLDL)-TG secretion assays revealed that hepatic ChREBP knockdown reduced downstream glycolysis and de novo lipogenesis but also strongly suppressed hepatic VLDL lipidation, hence promoting the storage of "old fat." Interestingly, enhanced VLDL-TG secretion in shSCR-treated L-G6pc-/- mice associated with a ChREBP-dependent induction of the VLDL lipidation proteins microsomal TG transfer protein and transmembrane 6 superfamily member 2 (TM6SF2), the latter being confirmed by ChIP-qPCR. CONCLUSIONS: Attenuation of hepatic ChREBP induction in GSD 1a liver aggravates hepatomegaly because of further accumulation of glycogen and lipids as a result of reduced glycolysis and suppressed VLDL-TG secretion. TM6SF2, critical for VLDL formation, was identified as a ChREBP target in mouse liver. Altogether, our data show that enhanced ChREBP activity limits NAFLD development in GSD 1a by balancing hepatic TG production and secretion.
Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Doença de Depósito de Glicogênio Tipo I/complicações , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Dependovirus/genética , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Glucose-6-Fosfatase/genética , Glicogênio/metabolismo , Doença de Depósito de Glicogênio Tipo I/genética , Doença de Depósito de Glicogênio Tipo I/metabolismo , Glicólise , Hepatócitos , Humanos , Lipogênese , Lipoproteínas VLDL/metabolismo , Masculino , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , RNA Interferente Pequeno/genética , Triglicerídeos/metabolismoRESUMO
It is a long-standing enigma how glycogen storage disease (GSD) type I patients retain a limited capacity for endogenous glucose production despite the loss of glucose-6-phosphatase activity. Insight into the source of residual endogenous glucose production is of clinical importance given the risk of sudden death in these patients, but so far contradictory mechanisms have been proposed. We investigated glucose-6-phosphatase-independent endogenous glucose production in hepatocytes isolated from a liver-specific GSD Ia mouse model (L-G6pc-/- mice) and performed real-time analysis of hepatic glucose fluxes and glycogen metabolism in L-G6pc-/- mice using state-of-the-art stable isotope methodologies. Here we show that G6pc-deficient hepatocytes are capable of producing glucose. In vivo analysis of hepatic glucose metabolism revealed that the hepatic glucokinase flux was decreased by 95% in L-G6pc-/- mice. It also showed increased glycogen phosphorylase flux in L-G6pc-/- mice, which is coupled to the release of free glucose through glycogen debranching. Although the ex vivo activities of debranching enzyme and lysosomal acid maltase, two major hepatic α-glucosidases, were unaltered in L-G6pc-/- mice, pharmacological inhibition of α-glucosidase activity almost completely abolished residual glucose production by G6pc-deficient hepatocytes. CONCLUSION: Our data indicate that hepatocytes contribute to residual glucose production in GSD Ia. We show that α-glucosidase activity, i.e. glycogen debranching and/or lysosomal glycogen breakdown, contributes to residual glucose production by GSD Ia hepatocytes. A strong reduction in hepatic GCK flux in L-G6pc-/- mice furthermore limits the phosphorylation of free glucose synthesized by G6pc-deficient hepatocytes, allowing the release of glucose into the circulation. The almost complete abrogation of GCK flux in G6pc-deficient liver also explains the contradictory reports on residual glucose production in GSD Ia patients. (Hepatology 2017;66:2042-2054).
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Glucose/metabolismo , Doença de Depósito de Glicogênio Tipo I/metabolismo , Hepatócitos/metabolismo , Animais , Modelos Animais de Doenças , Galactose/metabolismo , Glucose-6-Fosfatase/genética , Glicerol/metabolismo , Masculino , Camundongos , alfa-Glucosidases/metabolismoRESUMO
Liver X receptor (LXR) agonists exert potent antiatherosclerotic actions but simultaneously induce excessive triglyceride (TG) accumulation in the liver. To obtain a detailed insight into the underlying mechanism of hepatic TG accumulation, we used a novel computational modeling approach called analysis of dynamic adaptations in parameter trajectories (ADAPT). We revealed that both input and output fluxes to hepatic TG content are considerably induced on LXR activation and that in the early phase of LXR agonism, hepatic steatosis results from only a minor imbalance between the two. It is generally believed that LXR-induced hepatic steatosis results from increased de novo lipogenesis (DNL). In contrast, ADAPT predicted that the hepatic influx of free fatty acids is the major contributor to hepatic TG accumulation in the early phase of LXR activation. Qualitative validation of this prediction showed a 5-fold increase in the contribution of plasma palmitate to hepatic monounsaturated fatty acids on acute LXR activation, whereas DNL was not yet significantly increased. This study illustrates that complex effects of pharmacological intervention can be translated into distinct patterns of metabolic regulation through state-of-the-art mathematical modeling.
Assuntos
Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Receptores Nucleares Órfãos/metabolismo , Animais , Aterosclerose/tratamento farmacológico , Simulação por Computador , Ácidos Graxos não Esterificados/metabolismo , Hidrocarbonetos Fluorados/farmacologia , Hidrocarbonetos Fluorados/toxicidade , Lipogênese , Lipoproteínas VLDL/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Receptores X do Fígado , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Modelos Biológicos , Receptores Nucleares Órfãos/agonistas , Receptores Nucleares Órfãos/deficiência , PPAR gama/deficiência , PPAR gama/genética , PPAR gama/metabolismo , Sulfonamidas/farmacologia , Sulfonamidas/toxicidade , Biologia de Sistemas , Triglicerídeos/metabolismoRESUMO
Humans vary substantially in their ability to learn new motor skills. Here, we examined inter-individual differences in learning to play the piano, with the goal of identifying relations to structural properties of white matter fiber tracts relevant to audio-motor learning. Non-musicians (n = 18) learned to perform three short melodies on a piano keyboard in a pure audio-motor training condition (vision of their own fingers was occluded). Initial learning times ranged from 17 to 120 min (mean ± SD: 62 ± 29 min). Diffusion-weighted magnetic resonance imaging was used to derive the fractional anisotropy (FA), an index of white matter microstructural arrangement. A correlation analysis revealed that higher FA values were associated with faster learning of piano melodies. These effects were observed in the bilateral corticospinal tracts, bundles of axons relevant for the execution of voluntary movements, and the right superior longitudinal fasciculus, a tract important for audio-motor transformations. These results suggest that the speed with which novel complex audio-motor skills can be acquired may be determined by variability in structural properties of white matter fiber tracts connecting brain areas functionally relevant for audio-motor learning.
Assuntos
Percepção Auditiva/fisiologia , Individualidade , Música , Desempenho Psicomotor/fisiologia , Ensino , Substância Branca/anatomia & histologia , Estimulação Acústica , Adolescente , Adulto , Anisotropia , Mapeamento Encefálico , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Masculino , Estimulação Luminosa , Adulto JovemRESUMO
The liver is generally considered as a relatively homogeneous organ containing four different cell types. It is however well-known that the liver is not homogeneous and consists of clearly demarcated metabolic zones. Hepatocytes from different zones show phenotypical heterogeneity in metabolic features, leading to zonation of metabolic processes across the liver acinus. Zonation of processes involved in glucose and fatty acid metabolism is rather flexible and therefore prone to change under (patho)physiological conditions. Hepatic zonation appears to play an important role in the segregation of the different metabolic pathways in the liver. As a consequence, perturbations in metabolic zonation may be a part of metabolic liver diseases. The metabolic syndrome is characterized by the inability of insulin to adequately suppress hepatic gluconeogenesis, leading to hyperglycemia, hyperinsulinemia and eventually to type II diabetes. As insulin promotes lipogenesis through the transcription factor sterol regulatory element binding protein (SREBP)-1c, one would expect that lipogenesis should also be impaired in insulin-resistant states. However, in the metabolic syndrome hepatic de novo lipogenesis is increased, leading to hyperlipidemia and hepatosteatosis, primarily in the pericentral zone. These observations suggest the co-existence of insulin resistant glucose metabolism and insulin sensitive lipid metabolism in the metabolic syndrome. Here we provide a theoretical framework to explain this so-called 'insulin signaling paradox' in the context of metabolic zonation of the liver.
Assuntos
Ácidos Graxos/metabolismo , Glucose/metabolismo , Fígado/metabolismo , Animais , Fígado Gorduroso/metabolismo , Humanos , Resistência à Insulina , Metabolismo dos Lipídeos , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica , Especificidade de Órgãos , Transdução de SinaisRESUMO
To investigate the cross-modal transfer of movement patterns necessary to perform melodies on the piano, 22 non-musicians learned to play short sequences on a piano keyboard by (1) merely listening and replaying (vision of own fingers occluded) or (2) merely observing silent finger movements and replaying (on a silent keyboard). After training, participants recognized with above chance accuracy (1) audio-motor learned sequences upon visual presentation (89±17%), and (2) visuo-motor learned sequences upon auditory presentation (77±22%). The recognition rates for visual presentation significantly exceeded those for auditory presentation (p<.05). fMRI revealed that observing finger movements corresponding to audio-motor trained melodies is associated with stronger activation in the left rolandic operculum than observing untrained sequences. This region was also involved in silent execution of sequences, suggesting that a link to motor representations may play a role in cross-modal transfer from audio-motor training condition to visual recognition. No significant differences in brain activity were found during listening to visuo-motor trained compared to untrained melodies. Cross-modal transfer was stronger from the audio-motor training condition to visual recognition and this is discussed in relation to the fact that non-musicians are familiar with how their finger movements look (motor-to-vision transformation), but not with how they sound on a piano (motor-to-sound transformation).