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BACKGROUND & AIMS: Plasma bile acids (BAs) have been extensively studied as pathophysiological actors in non-alcoholic steatohepatitis (NASH). However, results from clinical studies are often complicated by the association of NASH with type 2 diabetes (T2D), obesity, and insulin resistance (IR). Here, we sought to dissect the relationship between NASH, T2D, and plasma BA levels in a large patient cohort. METHODS: Four groups of patients from the Biological Atlas of Severe Obesity (ABOS) cohort (Clinical Trials number NCT01129297) were included based on the presence or absence of histologically evaluated NASH with or without coincident T2D. Patients were matched for BMI, homeostatic model assessment 2 (HOMA2)-assessed IR, glycated haemoglobin, age, and gender. To study the effect of IR and BMI on the association of plasma BA and NASH, patients from the HEPADIP study were included. In both cohorts, fasting plasma BA concentrations were measured. RESULTS: Plasma BA concentrations were higher in NASH compared with No-NASH patients both in T2D and NoT2D patients from the ABOS cohort. As we previously reported that plasma BA levels were unaltered in NASH patients of the HEPADIP cohort, we assessed the impact of BMI and IR on the association of NASH and BA on the combined BA datasets. Our results revealed that NASH-associated increases in plasma total cholic acid (CA) concentrations depend on the degree of HOMA2-assessed systemic IR, but not on ß-cell function nor on BMI. CONCLUSIONS: Plasma BA concentrations are elevated only in those NASH patients exhibiting pronounced IR. LAY SUMMARY: Non-alcoholic steatohepatitis (NASH) is a progressive liver disease that frequently occurs in patients with obesity and type 2 diabetes. Reliable markers for the diagnosis of NASH are needed. Plasma bile acids have been proposed as NASH biomarkers. Herein, we found that plasma bile acids are only elevated in patients with NASH when significant insulin resistance is present, limiting their utility as NASH markers.
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In addition to their well-known role in the control of cellular proliferation and cancer, cell cycle regulators are increasingly identified as important metabolic modulators. Several GWAS have identified SNPs near CDKN2A, the locus encoding for p16INK4a (p16), associated with elevated risk for cardiovascular diseases and type-2 diabetes development, two pathologies associated with impaired hepatic lipid metabolism. Although p16 was recently shown to control hepatic glucose homeostasis, it is unknown whether p16 also controls hepatic lipid metabolism. Using a combination of in vivo and in vitro approaches, we found that p16 modulates fasting-induced hepatic fatty acid oxidation (FAO) and lipid droplet accumulation. In primary hepatocytes, p16-deficiency was associated with elevated expression of genes involved in fatty acid catabolism. These transcriptional changes led to increased FAO and were associated with enhanced activation of PPARα through a mechanism requiring the catalytic AMPKα2 subunit and SIRT1, two known activators of PPARα. By contrast, p16 overexpression was associated with triglyceride accumulation and increased lipid droplet numbers in vitro, and decreased ketogenesis and hepatic mitochondrial activity in vivo Finally, gene expression analysis of liver samples from obese patients revealed a negative correlation between CDKN2A expression and PPARA and its target genes. Our findings demonstrate that p16 represses hepatic lipid catabolism during fasting and may thus participate in the preservation of metabolic flexibility.
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Proteínas Quinases Ativadas por AMP/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Ácidos Graxos/metabolismo , Fígado/metabolismo , Mitocôndrias Hepáticas/metabolismo , PPAR alfa/metabolismo , Transdução de Sinais , Sirtuína 1/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Animais , Inibidor p16 de Quinase Dependente de Ciclina/genética , Ácidos Graxos/genética , Estudo de Associação Genômica Ampla , Humanos , Gotículas Lipídicas/metabolismo , Camundongos , Camundongos Knockout , Mitocôndrias Hepáticas/genética , Obesidade/genética , Obesidade/metabolismo , Oxirredução , PPAR alfa/genética , Sirtuína 1/genéticaRESUMO
BACKGROUND & AIMS: Although the role of inflammation to combat infection is known, the contribution of metabolic changes in response to sepsis is poorly understood. Sepsis induces the release of lipid mediators, many of which activate nuclear receptors such as the peroxisome proliferator-activated receptor (PPAR)α, which controls both lipid metabolism and inflammation. We aimed to elucidate the previously unknown role of hepatic PPARα in the response to sepsis. METHODS: Sepsis was induced by intraperitoneal injection of Escherichia coli in different models of cell-specific Ppara-deficiency and their controls. The systemic and hepatic metabolic response was analyzed using biochemical, transcriptomic and functional assays. PPARα expression was analyzed in livers from elective surgery and critically ill patients and correlated with hepatic gene expression and blood parameters. RESULTS: Both whole body and non-hematopoietic Ppara-deficiency in mice decreased survival upon bacterial infection. Livers of septic Ppara-deficient mice displayed an impaired metabolic shift from glucose to lipid utilization resulting in more severe hypoglycemia, impaired induction of hyperketonemia and increased steatosis due to lower expression of genes involved in fatty acid catabolism and ketogenesis. Hepatocyte-specific deletion of PPARα impaired the metabolic response to sepsis and was sufficient to decrease survival upon bacterial infection. Hepatic PPARA expression was lower in critically ill patients and correlated positively with expression of lipid metabolism genes, but not with systemic inflammatory markers. CONCLUSION: During sepsis, Ppara-deficiency in hepatocytes is deleterious as it impairs the adaptive metabolic shift from glucose to FA utilization. Metabolic control by PPARα in hepatocytes plays a key role in the host defense against infection. LAY SUMMARY: As the main cause of death in critically ill patients, sepsis remains a major health issue lacking efficacious therapies. While current clinical literature suggests an important role for inflammation, metabolic aspects of sepsis have mostly been overlooked. Here, we show that mice with an impaired metabolic response, due to deficiency of the nuclear receptor PPARα in the liver, exhibit enhanced mortality upon bacterial infection despite a similar inflammatory response, suggesting that metabolic interventions may be a viable strategy for improving sepsis outcomes.
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Adaptação Fisiológica , Fígado/metabolismo , PPAR alfa/fisiologia , Sepse/metabolismo , Animais , Infecções Bacterianas/metabolismo , Ácidos Graxos/metabolismo , Glucose/metabolismo , Humanos , Inflamação/etiologia , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Context: Bile acids (BAs) are signaling molecules controlling energy homeostasis that can be both toxic and protective for the liver. BA alterations have been reported in obesity, insulin resistance (IR), and nonalcoholic steatohepatitis (NASH). However, whether BA alterations contribute to NASH independently of the metabolic status is unclear. Objective: To assess BA alterations associated with NASH independently of body mass index and IR. Design and Setting: Patients visiting the obesity clinic of the Antwerp University Hospital (a tertiary referral facility) were recruited from 2006 to 2014. Patients: Obese patients with biopsy-proven NASH (n = 32) and healthy livers (n = 26) were matched on body mass index and homeostasis model assessment of IR. Main Outcome Measures: Transcriptomic analyses were performed on liver biopsies. Plasma concentrations of 21 BA species and 7α-hydroxy-4-cholesten-3-one, a marker of BA synthesis, were determined by liquid chromatography-tandem mass spectrometry. Plasma fibroblast growth factor 19 was measured by enzyme-linked immunosorbent assay. Results: Plasma BA concentrations did not correlate with any hepatic lesions, whereas, as previously reported, primary BA strongly correlated with IR. Transcriptomic analyses showed unaltered hepatic BA metabolism in NASH patients. In line, plasma 7α-hydroxy-4-cholesten-3-one was unchanged in NASH. Moreover, no sign of hepatic BA accumulation or activation of BA receptors-farnesoid X, pregnane X, and vitamin D receptors-was found. Finally, plasma fibroblast growth factor 19, secondary-to-primary BA, and free-to-conjugated BA ratios were similar, suggesting unaltered intestinal BA metabolism and signaling. Conclusions: In obese patients, BA alterations are related to the metabolic phenotype associated with NASH, especially IR, but not liver necroinflammation.
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Ácidos e Sais Biliares/metabolismo , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Adulto , Estudos de Casos e Controles , Feminino , Regulação da Expressão Gênica , Humanos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Obesidade/complicações , Obesidade/epidemiologiaRESUMO
Fatty liver diseases are complications of the metabolic syndrome associated with obesity, insulin resistance and low grade inflammation. Our aim was to uncover mechanisms contributing to hepatic complications in this setting. We used foz/foz mice prone to obesity, insulin resistance and progressive fibrosing non-alcoholic steatohepatitis (NASH). Foz/foz mice are hyperphagic but wild-type (WT)-matched calorie intake failed to protect against obesity, adipose inflammation and glucose intolerance. Obese foz/foz mice had similar physical activity level but reduced energy expenditure. Thermogenic adaptation to high-fat diet (HFD) or to cold exposure was severely impaired in foz/foz mice compared with HFD-fed WT littermates due to lower sympathetic tone in their brown adipose tissue (BAT). Intermittent cold exposure (ICE) restored BAT function and thereby improved glucose tolerance, decreased fat mass and liver steatosis. We conclude that failure of BAT adaptation drives the metabolic complications of obesity in foz/foz mice, including development of liver steatosis. Induction of endogenous BAT function had a significant therapeutic impact on obesity, glucose tolerance and liver complications and is a potential new avenue for therapy of non-alcoholic fatty liver disease (NAFLD).
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Síndrome Metabólica/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Obesidade/fisiopatologia , Termogênese/fisiologia , Tecido Adiposo Marrom/fisiopatologia , Animais , Restrição Calórica , Temperatura Baixa , Modelos Animais de Doenças , Ingestão de Energia , Metabolismo Energético/fisiologia , Intolerância à Glucose/fisiopatologia , Masculino , Síndrome Metabólica/etiologia , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/complicações , Consumo de Oxigênio/fisiologia , Condicionamento Físico Animal/fisiologiaRESUMO
Observational studies have reported different effects of adiposity on cardiovascular risk factors across age and sex. Since cardiovascular risk factors are enriched in obese individuals, it has not been easy to dissect the effects of adiposity from those of other risk factors. We used a Mendelian randomization approach, applying a set of 32 genetic markers to estimate the causal effect of adiposity on blood pressure, glycemic indices, circulating lipid levels, and markers of inflammation and liver disease in up to 67,553 individuals. All analyses were stratified by age (cutoff 55 years of age) and sex. The genetic score was associated with BMI in both nonstratified analysis (P = 2.8 × 10(-107)) and stratified analyses (all P < 3.3 × 10(-30)). We found evidence of a causal effect of adiposity on blood pressure, fasting levels of insulin, C-reactive protein, interleukin-6, HDL cholesterol, and triglycerides in a nonstratified analysis and in the <55-year stratum. Further, we found evidence of a smaller causal effect on total cholesterol (P for difference = 0.015) in the ≥55-year stratum than in the <55-year stratum, a finding that could be explained by biology, survival bias, or differential medication. In conclusion, this study extends previous knowledge of the effects of adiposity by providing sex- and age-specific causal estimates on cardiovascular risk factors.
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Adiposidade/fisiologia , Envelhecimento/fisiologia , Doenças Cardiovasculares/metabolismo , Pressão Sanguínea , Proteína C-Reativa/metabolismo , HDL-Colesterol/sangue , HDL-Colesterol/metabolismo , Feminino , Humanos , Insulina/sangue , Interleucina-6 , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Triglicerídeos/sangue , Triglicerídeos/metabolismoRESUMO
Human hepatocytes are used for liver cell therapy, but the small number of engrafting cells limits the benefit of cell transplantation. We tested whether cotransplantation of hepatocytes with hepatic stellate cells (HSCs) could improve hepatocyte engraftment in vivo. Human primary hepatocytes were transplanted into SCID mice either alone or in a mixture with HSCs (quiescent or after culture activation) or LX-2 cells (ratio 20:1). Four weeks after transplantation into mouse livers, human albumin-positive (huAlb(+)) hepatocytes were found scattered. When cotransplanted in a mixture with HSCs or LX-2 cells, huAlb(+) hepatocytes formed clusters and were more numerous occupying 2- to 5.9-fold more surface on the tissue section than in livers transplanted with hepatocytes alone. Increased huAlb mRNA expression in livers transplanted with the cell mixtures confirmed those results. The presence of HSCs increased the number of hepatocytes entrapped in the host liver at an early time point posttransplantation but not their proliferation in situ as assessed by cumulative incorporation of BrdU. Importantly, 4 weeks posttransplantation, we found no accumulation of αSMA(+)-activated HSCs or collagen deposition. To follow the fate of transplanted HSCs, HSCs derived from GFP(+) mice were injected into GFP(-) littermates: 17 h posttransplant, GFP(+) HSCs were found in the sinusoids, without proliferating or actively producing ECM; they were undetectable at later time points. Coculture with HSCs improved the number of adherent hepatocytes, with best attachment obtained when hepatocytes were seeded in contact with activated HSCs. In vivo, cotransplantation of hepatocytes with HSCs into a healthy liver recipient does not generate fibrosis, but significantly improves the engraftment of hepatocytes, probably by ameliorating cell homing.
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Terapia Baseada em Transplante de Células e Tecidos/métodos , Células Estreladas do Fígado/transplante , Hepatócitos/transplante , Cirrose Hepática/prevenção & controle , Adolescente , Albuminas/biossíntese , Albuminas/genética , Animais , Adesão Celular/fisiologia , Proliferação de Células , Células Cultivadas , Criança , Pré-Escolar , Técnicas de Cocultura , Criopreservação , Modelos Animais de Doenças , Feminino , Proteínas de Fluorescência Verde , Células Estreladas do Fígado/citologia , Hepatócitos/citologia , Humanos , Recém-Nascido , Fígado/citologia , Masculino , Camundongos , Camundongos SCID , Camundongos Transgênicos , Pessoa de Meia-Idade , RNA Mensageiro/biossíntese , Transplante HeterólogoRESUMO
Non-alcoholic fatty liver (steatosis) and steatohepatitis [non-alcoholic steatohepatitis (NASH)] are hepatic complications of the metabolic syndrome. Endoplasmic reticulum (ER) stress is proposed as a crucial disease mechanism in obese and insulin-resistant animals (such as ob/ob mice) with simple steatosis, but its role in NASH remains controversial. We therefore evaluated the role of ER stress as a disease mechanism in foz/foz mice, which develop both the metabolic and histological features that mimic human NASH. We explored ER stress markers in the liver of foz/foz mice in response to a high-fat diet (HFD) at several time points. We then evaluated the effect of treatment with an ER stress inducer tunicamycin, or conversely with the ER protectant tauroursodeoxycholic acid (TUDCA), on the metabolic and hepatic features. foz/foz mice are obese, glucose intolerant and develop NASH characterized by steatosis, inflammation, ballooned hepatocytes and apoptosis from 6 weeks of HFD feeding. This was not associated with activation of the upstream unfolded protein response [phospho-eukaryotic initiation factor 2α (eIF2α), inositol-requiring enzyme 1α (IRE1α) activity and spliced X-box-binding protein 1 (Xbp1)]. Activation of c-Jun N-terminal kinase (JNK) and up-regulation of activating transcription factor-4 (Atf4) and CCAAT/enhancer-binding protein-homologous protein (Chop) transcripts were however compatible with a 'pathological' response to ER stress. We tested this by using intervention experiments. Induction of chronic ER stress failed to worsen obesity, glucose intolerance and NASH pathology in HFD-fed foz/foz mice. In addition, the ER protectant TUDCA, although reducing steatosis, failed to improve glucose intolerance, hepatic inflammation and apoptosis in HFD-fed foz/foz mice. These results show that signals driving hepatic inflammation, apoptosis and insulin resistance are independent of ER stress in obese diabetic mice with steatohepatitis.
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Dieta Hiperlipídica , Estresse do Retículo Endoplasmático , Fígado Gorduroso/metabolismo , Resistência à Insulina , Animais , Glicemia , Proteínas de Ciclo Celular , Proteínas de Ligação a DNA/genética , Fígado Gorduroso/patologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica , FenótipoRESUMO
UNLABELLED: The pathophysiology of nonalcoholic steatohepatitis (NASH) should be approached as a multifactorial process. In several stages of NASH, a link between disease progression and hepatic microvasculature changes can be made. In this study we investigated the role of angiogenesis in two mouse models for NASH, and the effect of a preventive and therapeutic antiangiogenic treatment in a diet-induced mouse model for NASH. Protein and RNA levels of angiogenic and inflammatory factors were significantly up-regulated in the liver of C56BL/6 and db/db mice with NASH at different timepoints. To examine the effect of angiogenic factors on the disease progression of NASH, a prevention and treatment study was set up, blocking the placental growth factor (PlGF) or vascular endothelial growth factor receptor 2 (VEGFR2). Our study showed that treatment prevents the progression of NASH by attenuating steatosis and inflammation, both in a preventive and therapeutic setting, thereby confirming the hypothesis that angiogenic factors play an early role in the disease progression from steatosis to NASH. Anti-PlGF (αPlGF) did not significantly improve liver histology. Vascular corrosion casting showed a more disrupted liver vasculature in mice with NASH compared to controls. Treatment with αVEGFR2 showed an improvement of the liver vasculature. Moreover, fat-laden primary hepatocytes treated with αVEGFR2 stored significantly less lipids. CONCLUSION: Our results demonstrate that there is an increased expression of angiogenic factors in the liver in different mouse models for NASH. We found that VEGFR2 blockage attenuates steatosis and inflammation in a diet-induced mouse model for NASH in a preventive and therapeutic setting. Our findings warrant further investigation of the role of angiogenesis in the pathophysiology in NASH.
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Modelos Animais de Doenças , Progressão da Doença , Fígado Gorduroso/fisiopatologia , Neovascularização Patológica/fisiopatologia , Fator A de Crescimento do Endotélio Vascular/fisiologia , Inibidores da Angiogênese/farmacologia , Animais , Células Cultivadas , Deficiência de Colina/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Fígado Gorduroso/etiologia , Fígado Gorduroso/prevenção & controle , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Hepatócitos/fisiologia , Técnicas In Vitro , Metabolismo dos Lipídeos/fisiologia , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/fisiopatologia , Metionina/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Mutantes , Hepatopatia Gordurosa não Alcoólica , Fator de Crescimento Placentário , Proteínas da Gravidez/efeitos dos fármacos , Proteínas da Gravidez/fisiologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/efeitos dos fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/fisiologiaRESUMO
BACKGROUND & AIMS: Self-renewal of mature hepatocytes promotes homeostasis and regeneration of adult liver. However, recent studies have indicated that liver progenitor cells (LPC) could give rise to hepatic epithelial cells during normal turnover of the liver and after acute injury. We investigated the capacity of LPC to differentiate into hepatocytes in vivo and contribute to liver regeneration. METHODS: We performed lineage tracing experiments, using mice that express tamoxifen-inducible Cre recombinase under control of osteopontin regulatory region crossed with yelow fluorescent protein reporter mice, to follow the fate of LPC and biliary cells. Adult mice received partial (two-thirds) hepatectomy, acute or chronic administration of carbon tetrachloride (CCl(4)), choline-deficient diet supplemented with ethionine, or 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet. RESULTS: LPC and/or biliary cells generated 0.78% and 2.45% of hepatocytes during and upon recovery of mice from liver injury, respectively. Repopulation efficiency by LPC and/or biliary cells increased when extracellular matrix and laminin deposition were reduced. The newly formed hepatocytes integrated into hepatic cords, formed biliary canaliculi, expressed hepato-specific enzymes, accumulated glycogen, and proliferated in response to partial hepatectomy, as neighboring native hepatocytes. By contrast, LPC did not contribute to hepatocyte regeneration during normal liver homeostasis, in response to surgical or toxic loss of liver mass, during chronic liver injury (CCl(4)-induced), or during ductular reactions. CONCLUSIONS: LPC or biliary cells terminally differentiate into functional hepatocytes in mice with liver injury.
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Diferenciação Celular/fisiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Hepatócitos/citologia , Regeneração Hepática/fisiologia , Fígado/citologia , Células-Tronco/citologia , Animais , Tetracloreto de Carbono/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Deficiência de Colina/complicações , Transição Epitelial-Mesenquimal/fisiologia , Feminino , Hepatectomia/efeitos adversos , Homeostase/fisiologia , Fígado/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos , Modelos AnimaisRESUMO
BACKGROUND: Thyroid hormones (THs) exert multiple biological roles including effects on the cardiovascular system (lipid profile, blood pressure (BP) and cardiac output). The lipid-lowering actions of TH are mediated by the TH receptor-ß whereas the mechanisms explaining the BP variations concomitant with the thyroid disorders are less understood. As the TH receptor-α (TR-α) has been associated with many of TH actions on the cardiovascular system in mice models, we hypothesized that it could be involved in the latter. We thus tested whether polymorphisms in TR-α (THRA gene) could be associated with BP level variation. Secondarily, we tested for association with coronary heart disease (CHD) risk. METHODS: We analyzed the associations between five THRA polymorphisms and (i) BP level in two population-based studies (MONICA Lille n = 1,155; MONICA Toulouse n = 1,170) and (ii) the risk of CHD in two case-control studies (Lille CHD n = 558 cases/568 controls; PRIME n = 527 cases/584 controls). RESULTS: Individuals carrying the rs939348 T allele had higher systolic BP (~+1.3 mm Hg) than CC individuals in both the MONICA Lille (P = 0.02) and Toulouse (P = 0.03) studies. The odds ratio (OR) for hypertension was 1.25 (P = 0.02) in the combined sample. Concerning the CHD risk, no significant association could be detected. CONCLUSIONS: For the first time, our study showed associations between the THRA rs939348 polymorphism and systolic BP and the risk of hypertension but not with CHD, although we admit that the statistical power available to study any relationship with CHD was very limited. Further larger association studies are needed to confirm our findings.
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Pressão Sanguínea/genética , Doença das Coronárias/etiologia , Hipertensão/genética , Receptores alfa dos Hormônios Tireóideos/genética , Adulto , Doença das Coronárias/genética , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , RiscoRESUMO
OBJECTIVE: Genetic variability in the NR1H3 gene (encoding LXRα) and in several of its target genes is associated with serum HDL-cholesterol (HDL-C) concentrations. We sought to assess if these associations could be detected in adolescents. METHODS: Thirty-nine polymorphisms in NR1H3, ABCA1, APOE, CETP, PLTP and LPL were analysed in the HELENA study (n = 1144 European adolescents). RESULTS: The minor alleles of rs11039155 in NR1H3, rs2575879 in ABCA1, rs708272, rs17231506 and rs5882 in CETP and rs328 in LPL were associated with higher serum HDL-C concentrations (p ≤ 0.0012). The minor alleles of rs12221497 in NR1H3, rs1800978 in ABCA1 and the APOE É4 allele were associated with lower HDL-C concentrations (p ≤ 0.01). The combined set of associated polymorphisms accounted for â¼6.6% of the variance in HDL-C. CONCLUSION: We report for the first time that polymorphisms in NR1H3 and its target genes ABCA1, APOE, CETP and LPL contribute to the genetic variance for HDL-C concentrations in adolescence.
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HDL-Colesterol/sangue , Receptores Nucleares Órfãos/genética , Polimorfismo de Nucleotídeo Único , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Adolescente , Apolipoproteínas E/genética , Biomarcadores/sangue , Distribuição de Qui-Quadrado , Proteínas de Transferência de Ésteres de Colesterol/genética , Estudos Transversais , Europa (Continente) , Feminino , Frequência do Gene , Haplótipos , Humanos , Desequilíbrio de Ligação , Lipase Lipoproteica/genética , Receptores X do Fígado , Masculino , Fenótipo , Proteínas de Transferência de Fosfolipídeos/genéticaRESUMO
Obesity and the metabolic syndrome are systemic inflammatory diseases reaching epidemic proportions. Contemporary changes in human nutrition occurred characterized by increased consumption of fat and of vegetable oils rich in n-6 polyunsaturated fatty acids (PUFAs) together with decrease in n-3 PUFA-rich foods, resulting in an n-6/n-3 ratio of 10-20/1 in Western diet for a ratio around 1/1 in the diet of our ancestors. The literature provides compelling evidence for the health benefit of n-3 PUFA consumption on inflammation and metabolic syndrome prevention and treatment. Such evidence led to the establishment of comprehensive recommendations. However, we show here that, both in collective catering proposed to children and in hospital diet, it is not straightforward to meet such recommendations. Willingness of governments to institute changes, with accountable decisions on catering, nutritional education, and food processing, is required to face our neglected responsibility in promoting balanced diet and consumption of foods rich in essential nutrients in the general population.
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BACKGROUND: The liver X receptors (LXR) α and ß regulate lipid and carbohydrate homeostasis and inflammation. Lxrßâ»/â» mice are glucose intolerant and at the same time lean. We aimed to assess the associations between single nucleotide polymorphisms (SNPs) in LXRß and risk of type 2 diabetes mellitus (T2DM), obesity and related traits in 3 separate cohort studies. METHODS: Twenty LXRß SNPs were identified by sequencing and genotyped in the HUNT2 adult nested case-control study for T2DM (n = 835 cases/1986 controls). Five tag-SNPs (rs17373080, rs2695121, rs56151148, rs2303044 and rs3219281), covering 99.3% of the entire common genetic variability of the LXRß gene were identified and genotyped in the French MONICA adult study (n = 2318) and the European adolescent HELENA cross-sectional study (n = 1144). In silico and in vitro functionality studies were performed. RESULTS: We identified suggestive or significant associations between rs17373080 and the risk of (i) T2DM in HUNT2 (OR = 0.82, p = 0.03), (ii) obesity in MONICA (OR = 1.26, p = 0.05) and (iii) overweight/obesity in HELENA (OR = 1.59, p = 0.002). An intron 4 SNP (rs28514894, a perfect proxy for rs17373080) could potentially create binding sites for hepatic nuclear factor 4 alpha (HNF4α) and nuclear factor 1 (NF1). The C allele of rs28514894 was associated with ~1.25-fold higher human LXRß basal promoter activity in vitro. However, no differences between alleles in terms of DNA binding and reporter gene transactivation by HNF4α or NF1 were observed. CONCLUSIONS: Our results suggest that rs17373080 in LXRß is associated with T2DM and obesity, maybe via altered LXRß expression.
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Diabetes Mellitus Tipo 2/genética , Obesidade/genética , Receptores Nucleares Órfãos/genética , Adolescente , Adulto , Idoso , Alelos , Sítios de Ligação , Estudos de Coortes , Europa (Continente) , Feminino , França , Predisposição Genética para Doença , Genótipo , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Íntrons , Receptores X do Fígado , Masculino , Pessoa de Meia-Idade , Fatores de Transcrição NFI/metabolismo , Noruega , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNARESUMO
We selected twenty genes from the "Top Results" list on the AlzGene database website and assessed their association with risk of developing Alzheimer's disease (AD) in a large, genome-wide association study (using 526 SNPs from 2,032 AD cases and 5,328 controls) performed in France. The APOE, CLU, PICALM, and CR1 loci were excluded, since they had already been extensively analyzed. Ten genes/loci (TFAM, SORL1, CHRNB2, SORCS1, DAPK1, MTHFR, GWA 14q32.13, BDNF, NEDD9, and CH25H) showed weak nominal association with AD risk, in line with previous studies. In the remaining ten genes/loci (TNK1, ACE, CST3, IL1B, hCG2039140, PRNP, GAB2, LOC651924, IL1A, and TF), no single nucleotide polymorphisms were associated in our dataset. Of the genes showing nominal association in our cohorts, TFAM and CHRNB2 appear particularly interesting and warrant further genetic and functional follow-up analyses.
Assuntos
Doença de Alzheimer/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/psicologia , DNA/genética , Bases de Dados Genéticas , Feminino , França , Frequência do Gene , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Escalas de Graduação PsiquiátricaRESUMO
OBJECTIVE: To examine whether physical activity attenuates the effect of the FTO rs9939609 polymorphism on body fat estimates in adolescents. DESIGN: Cross-sectional study. SETTING: Athens, Greece; Dortmund, Germany; Ghent, Belgium; Heraklion, Greece; Lille, France; Pécs, Hungary; Rome, Italy; Stockholm, Sweden; Vienna, Austria; and Zaragoza, Spain, from October 2006 to December 2007. PARTICIPANTS: Adolescents from the Healthy Lifestyle in Europe by Nutrition in Adolescence Cross-Sectional Study (n = 752). MAIN EXPOSURE: Physical activity. MAIN OUTCOME MEASURES: The FTO rs9939609 polymorphism was genotyped. Physical activity was assessed by accelerometry. We measured weight, height, waist circumference, and triceps and subscapular skinfolds; body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]) and body fat percentage were calculated. RESULTS: The A allele of the FTO polymorphism was significantly associated with higher BMI (+0.42 per risk allele), higher body fat percentage (+1.03% per risk allele), and higher waist circumference (+0.85 cm per risk allele). We detected significant or borderline gene x physical activity interactions for the studied body fat estimates (for interaction, P = .02, .06, and .10 for BMI, body fat percentage, and waist circumference, respectively). Indeed, the effect of the FTO rs9939609 polymorphism on these body fat parameters was much lower in adolescents who met the daily physical activity recommendations (ie, >/=60 min/d of moderate to vigorous physical activity) compared with those who did not: +0.17 vs +0.65 per risk allele in BMI, respectively; +0.40% vs +1.70% per risk allele in body fat percentage, respectively; and +0.60 vs +1.15 cm per risk allele in waist circumference, respectively. CONCLUSION: Adolescents meeting the daily physical activity recommendations may overcome the effect of the FTO rs9939609 polymorphism on obesity-related traits.
Assuntos
Tecido Adiposo/fisiologia , Distribuição da Gordura Corporal , Exercício Físico , Obesidade/prevenção & controle , Polimorfismo Genético , Proteínas/genética , Adolescente , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Índice de Massa Corporal , Estudos Transversais , Europa (Continente) , Feminino , Humanos , Masculino , Obesidade/genética , Circunferência da CinturaRESUMO
CD36 is a membrane receptor with a wide variety of functions, including the regulation of energy metabolism, fat storage, and adipocyte differentiation. To assess the relationship between CD36 gene single-nucleotide polymorphisms (SNPs) and obesity in adolescents, we evaluated the relationship between CD36 SNPs and the risk of obesity in a case-control study composed of 307 obese (age = 15.0 +/- 1.1 years) and 339 normal-weight adolescents (age = 14.6 +/- 1.1 years). To validate the results, we assessed the relation between the same SNPs and percentage of body fat (BF%) and BMI in 1,151 European adolescents (age = 14.8 +/- 1.4 years). SNPs with a minor allele frequency >0.10 were selected to tag CD36. Genotyping was performed on an Illumina system. Four SNPs (rs3211867, rs3211883, rs3211908, and rs1527483) were associated with increased risk of obesity in the case-control study (odds ratio (OR) (95% confidence interval)): 1.96 (1.26-3.04], P = 0.003; 1.73 (1.16-2.59), P = 0.007; 2.42 (1.47-4.01), P = 0.0005 and 1.95 (1.25-3.05), P = 0.003, respectively). The same four SNPs were associated with higher BMI (P < 0.05) and BF% (P < 0.04) in the validation study. Further analyses identified a haplotype (frequency: 0.05) carrying the minor allele of these SNPs as being associated with obesity (OR: 2.28; P = 0.0008) in the case-control study and with excess adiposity (i.e., higher BF% (P = 0.03) and BMI (P = 0.04)) in the validation study. Our data suggest that genetic variability at the CD36 gene locus could be associated with body weight variability in European adolescents but these findings require replication.
Assuntos
Antígenos CD36/genética , Obesidade/epidemiologia , Obesidade/genética , População Branca/genética , População Branca/estatística & dados numéricos , Adolescente , Índice de Massa Corporal , Peso Corporal/genética , Estudos de Casos e Controles , Metabolismo Energético/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença/epidemiologia , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo ÚnicoRESUMO
CONTEXT: Plasma-borne angiopoietin-like proteins (ANGPTL) act as endocrine factors on their target tissues. Because ANGPTL3 and ANGPTL4 play important roles in lipid metabolism and the regulation of adiposity in mice, we hypothesized that genetic variability at the ANGPTL3 and ANGPTL4 genes loci might influence lipid metabolism and fat deposition in humans. OBJECTIVE: The aim of the study was to examine the association between ANGPTL3 and ANGPTL4 genetic polymorphisms and metabolic phenotypes in adolescent and adult samples. DESIGN AND PARTICIPANTS: Two independent population-based studies, one composed of 1144 adolescents (mean age, 14.8 +/- 1.4 yr) from nine European countries (the HELENA study) and the other composed of 1155 adults (age range, 35-65 yr) from Northern France (the MONICA Lille study), were genotyped for one ANGPTL3 polymorphism and four ANGPTL4 polymorphisms. RESULTS: The ANGPTL3 rs11207997 polymorphism (minor allele frequency, 0.32) was associated with lower plasma HDL-cholesterol and apolipoprotein A-I levels in both adolescents (P = 0.0004, P = 0.00006, respectively) and adults (P = 0.03, P = 0.02, respectively). The ANGPTL4 rs4076317 polymorphism (minor allele frequency, 0.29) was associated with a higher percentage of body fat (P = 0.02) in adolescents and a higher waist-to-hip ratio (in interaction with the peroxisome proliferator-activated receptor gamma Pro12Ala polymorphism) in adults (P = 0.0004). CONCLUSION: The present study underlines the role of ANGPTL3 in HDL-cholesterol metabolism as early as in adolescence. Our data also suggest possible associations between ANGPTL4 polymorphisms and body fat, but these findings require replication.
Assuntos
Adiposidade/genética , Angiopoietinas/genética , Metabolismo dos Lipídeos/genética , Adolescente , Adulto , Idoso , Proteína 3 Semelhante a Angiopoietina , Proteína 4 Semelhante a Angiopoietina , Proteínas Semelhantes a Angiopoietina , Animais , Antropometria , Estudos Transversais , Feminino , França/epidemiologia , Frequência do Gene , Variação Genética , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Atividade Motora , Fenótipo , Polimorfismo Genético/genética , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
We investigated the association between the rs9939609 (T>A) polymorphism in the FTO (fat mass- and obesity-associated) gene and obesity- and type 2 diabetes mellitus-related phenotypes in the French Multinational MONItoring of Trends and Determinants in CArdiovascular Disease (MONICA) Study (n = 3367). In the study, TA or AA subjects had higher body mass index (BMI) (P = .017), waist circumference (P = .017), and hip (P = .01) circumference in an A allele dose-dependent manner. The A allele was also significantly associated with higher plasma insulin levels (P = .05), higher insulin resistance index (homeostasis model assessment) (P = .02), and higher systolic blood pressure (P = .003); but these associations disappeared after adjustment for BMI. In the study, 598 subjects were obese (BMI >or=30 kg/m(2)); and 2769 subjects were not obese (BMI <30 kg/m(2)). Subjects bearing the A allele of rs9939609 had a higher risk of obesity (adjusted odds ratio [95% confidence interval] = 1.29 [1.06-1.58], P = .01) compared with TT subjects. Moreover, the homozygous AA genotype of rs9939609 was associated with a higher risk of type 2 diabetes mellitus (odds ratio = 1.45 [1.05-1.99], P = .02, 283 subjects with and 2601 subjects without type 2 diabetes mellitus), independently of BMI. In conclusion, the role of the A allele of the FTO rs9939609 polymorphism on the risk of obesity and type 2 diabetes mellitus was confirmed in the French MONICA Study.