RESUMEN
Aging is a risk factor in the development of many diseases, including liver-related diseases. The two aims of the present study were 1) to determine how aging affects liver health in mice in the absence of any interventions and 2) if degenerations observed in relation to blood endotoxin levels are critical in aging-associated liver degeneration. Endotoxin levels and markers of liver damage, mitochondrial dysfunction, insulin resistance, and apoptosis as well as the Toll-like receptor 4 (Tlr-4) signaling cascade were studied in liver tissue and blood, respectively, of 3- and 24-mo-old male C57BL/6J mice. In a second set of experiments, 3- to 4-mo-old and 14-mo-old female lipopolysaccharide-binding protein (LBP)-/- mice and littermates fed standard chow, markers of liver damage, insulin resistance, and mitochondrial dysfunction were assessed. Plasma activity of aspartate aminotransferase and histological signs of hepatic inflammation and fibrosis were significantly higher in old C57BL/6J mice than in young animals. The number of neutrophils, CD8α-positive cells, and mRNA expression of markers of apoptosis were also significantly higher in livers of old C57BL/6J mice compared with young animals, being also associated with a significant induction of hepatic Tlr-4 and LBP expression as well as higher endotoxin levels in peripheral blood. Compared with age-matched littermates, LBP-/- mice display less signs of senescence in liver. Taken together, our data suggest that, despite being fed standard chow, old mice developed liver inflammation and beginning fibrosis and that bacterial endotoxin may play a critical role herein.NEW & NOTEWORTHY Old age in mice is associated with marked signs of liver degeneration, hepatic inflammation, and fibrosis. Aging-associated liver degeneration is associated with elevated bacterial endotoxin levels and an induction of lipopolysaccharide-binding protein (LBP) and Toll-like receptor 4-dependent signaling cascades in liver tissue. Furthermore, in old aged LBP-/- mice, markers of senescence seem to be lessened, supporting the hypothesis that bacterial endotoxin levels might be critical in aging-associated decline of liver.
Asunto(s)
Proteínas de Fase Aguda/metabolismo , Envejecimiento , Proteínas Portadoras/metabolismo , Endotoxinas/sangre , Cirrosis Hepática/patología , Hígado/patología , Glicoproteínas de Membrana/metabolismo , Proteínas de Fase Aguda/genética , Animales , Apoptosis , Biomarcadores , Proteínas Portadoras/genética , Femenino , Regulación de la Expresión Génica , Glucosa/metabolismo , Inflamación/patología , Proteínas Sustrato del Receptor de Insulina/genética , Proteínas Sustrato del Receptor de Insulina/metabolismo , Hígado/metabolismo , Malato Deshidrogenasa/genética , Malato Deshidrogenasa/metabolismo , Masculino , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , ARN Mensajero , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismoRESUMEN
PURPOSE: Results of some epidemiological studies suggest that moderate alcohol consumption may be associated with a decreased risk to develop NAFLD. Here, the effect of the consumption of moderate beer and diluted ethanol, respectively, on the development of NAFLD were assessed. METHODS: Female C57BL/6J mice were fed a control diet (C-D) or a diet rich in fructose, fat and cholesterol (FFC) enriched isocalorically and isoalcoholically with beer (FFC + B) or plain ethanol (FFC + E) (2.5 g ethanol/kg body weight/day) for 7 weeks. Liver damage was assessed by histology using NAFLD activity score. Markers of inflammation, insulin resistance and adiponectin signaling were measured at mRNA and protein levels. Using J774A.1 cells as a model of Kupffer cells, the effect of alcoholic beverages on adiponectin receptor 1 (Adipor1) was assessed. RESULTS: Hepatic triglyceride concentration, neutrophil granulocytes, iNOS protein concentrations and early signs of insulin resistance found in FFC-fed mice were significantly attenuated in FFC+ B-fed mice (P < 0.05 for all). These findings were associated with a super-induction of Adipor1 mRNA expression (+ ~ 18-fold compared to all other groups) and a decrease of markers of lipid peroxidation in liver tissue of FFC + B-fed mice when compared to FFC-fed animals. Similar differences were not found between FFC- and FFC+ E-fed mice. Expression of Adipor1 was also super-induced (7.5-fold) in J774A.1 cells treated with beer (equivalent to 2 mmol/L ethanol). CONCLUSIONS: These data suggest that moderate intake of fermented alcoholic beverages such as beer at least partially attenuates NAFLD development through mechanisms associated with hepatic AdipoR1 expression.
Asunto(s)
Adiponectina/metabolismo , Cerveza , Dieta/efectos adversos , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Transducción de Señal/efectos de los fármacos , Animales , Dieta/métodos , Modelos Animales de Enfermedad , Etanol/administración & dosificación , Femenino , Alimentos Fermentados , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/metabolismoRESUMEN
Dietary arginine (Arg) supplementation has been proposed to have positive effects on the development of liver diseases. In the present study, we investigate if an oral Arg supplementation in diet protects mice fed a fructose, fat and cholesterol enriched Western-style diet (WSD) from the development of non-alcoholic steatohepatitis (NASH). Female C57BL/6J mice were fed a liquid control diet or a liquid WSD ± Arg (2.49 g/kg body weight/day) for 6 weeks. Indices of liver injury, glucose metabolism and intestinal permeability were determined. While Arg supplementation had no effects on body weight gain, fasting blood glucose levels were significantly lower in WSD+Arg-fed mice than in C+Arg-fed animals. WSD-fed mice developed liver steatosis accompanied with inflammation, both being significantly attenuated in WSD+Arg-fed mice. These effects of Arg supplementation went along with a protection against WSD-induced decreased tight junction protein levels in the upper parts of the small intestine, increased levels of bacterial endotoxin in portal plasma as well as increased hepatic toll-like receptor-4 mRNA and 4-hydroxynonenal protein adduct levels. In conclusion, Arg supplementation may protect mice from the development of NASH.
Asunto(s)
Arginina/farmacología , Suplementos Dietéticos , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Administración Oral , Animales , Glucemia/metabolismo , Femenino , Intestino Delgado/metabolismo , Intestino Delgado/patología , Hígado/metabolismo , Hígado/patología , Ratones , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/patología , Uniones Estrechas/patología , Receptor Toll-Like 4/sangreRESUMEN
OBJECTIVE: Overfeeding with a high-fat and/or high-carbohydrate (CHO) diet is known to increase plasma concentrations of endotoxin (lipopolysaccharide [LPS]) that may lead to metabolic disturbances like insulin resistance. The impact of CHO quality (i.e., the glycemic index [GI]) independent of fat intake on metabolic endotoxemia remains unclear. In the present study, the effects of changes in energy balance and GI on plasma endotoxin were studied. METHODS: Fifteen healthy young men overconsumed diets containing 65% CHO and 20% fat for 1 week (OF; +50% of energy requirement) followed by 3 weeks of caloric restriction (CR; -50% of energy requirement) and were then randomized to 2 weeks hypercaloric refeeding (RF, +50% of energy requirement) with either a low- or high-GI (40 vs 74) diet. RESULTS: During OF, subjects gained 1.9 ± 0.7 kg body weight (+0.6 ± 0.8% fat mass) followed by a weight loss of 6.1 ± 0.8 kg (-2.0 ± 0.6% fat mass) and weight regain of 4.0 ± 0.6 kg (0.9 ± 0.8% fat mass). Fasting insulin and homeostasis model assessment-insulin resistance (HOMAIR) increased with OF and RF and decreased with CR, MatsudaISI decreased by 37% after RF (all p < 0.05). Endotoxin significantly increased by 30.8% with OF and by 24.7% with RF (both p < 0.05), whereas CR normalized endotoxin levels. No difference in endotoxin levels was observed between refeeding a hypercaloric high- or low-GI diet. Changes in endotoxin levels with RF were not related to changes in insulin sensitivity. CONCLUSION: A hypercaloric diet (OF and RF) increased plasma endotoxin irrespective of GI, whereas a negative energy balance did not reduce endotoxemia. Impaired insulin sensitivity with hypercaloric refeeding on a high-GI diet was not explained by metabolic endotoxemia.
Asunto(s)
Endotoxemia , Metabolismo Energético/fisiología , Índice Glucémico/fisiología , Adulto , Índice de Masa Corporal , Peso Corporal , Restricción Calórica , Dieta , Endotoxinas/sangre , Ingestión de Energía , Humanos , Hiperfagia , Resistencia a la Insulina , Lípidos/sangre , MasculinoRESUMEN
PURPOSE: Impairments of intestinal barrier function are discussed as risk factors for the development and progression of non-alcoholic fatty liver disease (NAFLD). Studies suggest an association between arginine/citrulline homeostasis and the development of liver damages. Here, the effect of an oral L-citrulline (Cit) supplement on the development of a Western-style diet (WSD)-induced NAFLD was determined in mice. METHODS: Female 6- to 8-week-old C57BL/6J mice were either pair-fed a liquid Western-style or control diet (C) ± 2.5 g/kg bodyweight Cit for 6 weeks (C + Cit or WSD + Cit). Indices of liver damage, glucose metabolism, intestinal barrier function and NO synthesis were measured. RESULTS: While bodyweight gain was similar between groups, markers of glucose metabolism like fasting blood glucose and HOMA index and markers of liver damage like hepatic triglyceride levels, number of neutrophils and plasminogen activator inhibitor-1 protein levels were significantly lower in WSD + Cit-fed mice when compared to WSD-fed mice only. Protein levels of the tight junction proteins occludin and zonula occludens-1 in duodenum were significantly lower in mice fed a WSD when compared to those fed a WSD + Cit (-~70 and -~60 %, respectively, P < 0.05), whereas portal endotoxin levels, concentration of 3-nitrotyrosine protein adducts in duodenum and toll-like receptor-4 mRNA expression in livers of WSD + Cit-fed mice were markedly lower than in WSD-fed mice (-~43 %, P = 0.056; -~80 and -~48 %, respectively, P < 0.05). CONCLUSION: Our data suggest that the protective effects of supplementing Cit on the development of NAFLD in mice are associated with a decreased translocation of endotoxin into the portal vein.
Asunto(s)
Citrulina/farmacología , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Biomarcadores/sangre , Peso Corporal , Dieta Occidental , Suplementos Dietéticos , Modelos Animales de Enfermedad , Duodeno/efectos de los fármacos , Duodeno/metabolismo , Endotoxinas/sangre , Femenino , Insulina/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Ocludina/genética , Ocludina/metabolismo , Inhibidor 1 de Activador Plasminogénico/genética , Inhibidor 1 de Activador Plasminogénico/metabolismo , Sustancias Protectoras/farmacología , Proteínas de Uniones Estrechas/genética , Proteínas de Uniones Estrechas/metabolismo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Triglicéridos/sangre , Proteína de la Zonula Occludens-1/genética , Proteína de la Zonula Occludens-1/metabolismoRESUMEN
BACKGROUND AND AIM: It has been suggested in several studies that an increased translocation of bacterial lipopolysaccharide (LPS) and, subsequently, an activation of toll-like receptor (TLR)-dependent signaling pathways in the liver may contribute to the development of non-alcoholic fatty liver disease. METHODS: Eight-week-old lipopolysaccharide-binding protein (LBP)-/- and wild-type (WT) mice were pair fed either a liquid diet rich in fat, fructose, and cholesterol (Western-style diet [WSD]) or a control liquid diet for 8 weeks. Parameters of liver injury, markers of TLR-4-dependent signaling pathway, and glucose/lipid metabolism were determined. RESULTS: Despite similar total caloric intake, weight gain, fasting blood glucose levels, and liver-to-bodyweight ratio, indices of liver damage determined by liver histology and transaminases were markedly lower in WSD-fed LBP-/- mice than in WSD-fed WT animals. In line with these findings, number of neutrophils, F4/80 positive cells, and plasminogen activator inhibitor 1 were only found to be significantly increased in livers of WSD-fed WT mice. While mRNA expressions of TLR-4 and myeloid differentiation primary response 88 were similar between WSD-fed groups, concentrations of inducible nitric oxide synthase protein and 4-hydroxynonenal protein adducts were significantly higher in livers of WSD-fed WT mice than in WSD-fed LBP-/- animals. Markers of lipid metabolism, for example, sterol regulatory element-binding protein 1c and fatty acid synthase per se, were significantly lower in livers of LBP-/- mice; however, mRNA expressions did not differ between controls and WSD-fed mice within the respective mouse strain. CONCLUSION: Taken together, our results suggest that LBP is a critical factor in the development of non-alcoholic fatty liver disease in mice.
Asunto(s)
Proteínas de Fase Aguda/deficiencia , Proteínas de Fase Aguda/fisiología , Proteínas Portadoras/fisiología , Lipopolisacáridos/metabolismo , Hígado/metabolismo , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/fisiología , Enfermedad del Hígado Graso no Alcohólico/etiología , Animales , Modelos Animales de Enfermedad , Glucosa/metabolismo , Metabolismo de los Lípidos , Ratones Endogámicos BALB C , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/genética , Transducción de Señal/fisiología , Receptores Toll-Like/metabolismoRESUMEN
AIM: Using a binge-drinking mouse model, we aimed to determine whether hops (Humulus lupulus) in beer is involved in the less damaging effects of acute beer consumption on the liver in comparison with ethanol. METHODS: Female C57BL/6 J mice were either fed one iso-alcoholic and iso-caloric bolus dose of ethanol, beer, beer without hops (6 g ethanol/kg body weight) or an iso-caloric bolus of maltodextrin control solution. Markers of steatosis, intestinal barrier function, activation of toll-like receptor 4 signaling cascades, lipid peroxidation and lipogenesis were determined in liver, small intestine and plasma 2 h and 12 h after acute alcohol ingestion. RESULTS: Alcohol-induced hepatic fat accumulation was significantly attenuated in mice fed beer whereas in those fed beer without hops, hepatic fat accumulation was similar to that found in ethanol-fed mice. While markers of intestinal barrier function e.g. portal endotoxin levels and lipogenesis only differed slightly between groups, hepatic concentrations of myeloid differentiation primary response gene 88, inducible nitric oxide synthase (iNOS) and plasminogen-activator inhibitor 1 protein as well as of 4-hydroxynonenal and 3-nitrotyrosine protein adducts were similarly elevated in livers of mice fed ethanol or beer without hops when compared with controls. Induction of these markers was markedly attenuated in mice fed hops-containing beer. CONCLUSION: Taken together, our data suggest that hops in beer markedly attenuated acute alcohol-induced liver steatosis in female mice through mechanisms involving a suppression of iNOS induction in the liver.
Asunto(s)
Cerveza , Hígado Graso/inducido químicamente , Hígado Graso/prevención & control , Humulus , Hígado/efectos de los fármacos , Animales , Cerveza/efectos adversos , Hígado Graso/metabolismo , Femenino , Humulus/metabolismo , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BLRESUMEN
In different pathophysiological conditions plasminogen activator inhibitor-1 (PAI-1) plasma concentrations are elevated. As dietary patterns are considered to influence PAI-1 concentration, we aimed to determine active PAI-1 plasma concentrations and mRNA expression in adipose tissue before and after consumption of a high-fat diet (HFD) and the impact of additive genetic effects herein in humans. For 6 weeks, 46 healthy, non-obese pairs of twins (aged 18-70) received a normal nutritionally balanced diet (ND) followed by an isocaloric HFD for 6 weeks. Active PAI-1 plasma levels and PAI-1 mRNA expression in subcutaneous adipose tissue were assessed after the ND and after 1 and 6 weeks of HFD. Active PAI-1 plasma concentrations and PAI-1 mRNA expression in adipose tissue were significantly increased after both 1 and 6 weeks of HFD when compared to concentrations determined after ND (p < .05), with increases of active PAI-1 being independent of gender, age, or changes of BMI and intrahepatic fat content, respectively. However, analysis of covariance suggests that serum insulin concentration significantly affected the increase of active PAI-1 plasma concentrations. Furthermore, the increase of active PAI-1 plasma concentrations after 6 weeks of HFD was highly heritable (47%). In contrast, changes in PAI-1 mRNA expression in fatty tissue in response to HFD showed no heritability and were independent of all tested covariates. In summary, our data suggest that even an isocaloric exchange of macronutrients - for example, a switch to a fat-rich diet - affects PAI-1 concentrations in humans and that this is highly heritable.
Asunto(s)
Tejido Adiposo/metabolismo , Grasas de la Dieta/administración & dosificación , Regulación de la Expresión Génica/efectos de los fármacos , Inhibidor 1 de Activador Plasminogénico , ARN Mensajero , Gemelos , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inhibidor 1 de Activador Plasminogénico/sangre , Inhibidor 1 de Activador Plasminogénico/genética , ARN Mensajero/biosíntesis , ARN Mensajero/genéticaRESUMEN
OBJECTIVE: Increased fasting blood ethanol levels, suggested to stem from an increased endogenous ethanol synthesis in the GI tract, are discussed to be critical in the development of non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to further delineate the mechanisms involved in the elevated blood ethanol levels found in patients with NAFLD. DESIGN: In 20 nutritionally and metabolically screened children displaying early signs of NAFLD and 29 controls (aged 5-8â years), ethanol plasma levels were assessed. Ethanol levels along the GI tract, in vena cava and portal vein, intestinal and faecal microbiota, and activity of alcohol dehydrogenase (ADH) and cytochrome P450 2E1 (CYP2E1) were measured in wild-type, ob/ob and anti-TNFα antibody (aT) treated ob/ob mice. RESULTS: Despite not differing in dietary pattern or prevalence of intestinal overgrowth, fasting ethanol levels being positively associated with measures of insulin resistance were significantly higher in children with NAFLD than in controls. Ethanol levels were similar in portal vein and chyme obtained from different parts of the GI tract between groups while ethanol levels in vena cava plasma were significantly higher in ob/ob mice. ADH activity was significantly lower in liver tissue obtained from ob/ob mice in comparison to wild-type controls and ob/ob mice treated with aT. CONCLUSIONS: Taken together, our data of animal experiments suggest that increased blood ethanol levels in patients with NAFLD may result from insulin-dependent impairments of ADH activity in liver tissue rather than from an increased endogenous ethanol synthesis. TRIAL REGISTRATION NUMBER: NCT01306396.
Asunto(s)
Alcohol Deshidrogenasa , Etanol , Resistencia a la Insulina/fisiología , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico , Alcohol Deshidrogenasa/sangre , Alcohol Deshidrogenasa/metabolismo , Animales , Índice de Masa Corporal , Niño , Preescolar , Citocromo P-450 CYP2E1/sangre , Etanol/sangre , Etanol/metabolismo , Femenino , Humanos , Masculino , Ratones , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Fenómenos Fisiológicos de la Nutrición , Estadística como AsuntoRESUMEN
Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide with universally accepted treatments still lacking. Oral supplementation of sodium butyrate (SoB) has been suggested to attenuate liver damage of various aetiologies. Our study aimed to further delineate mechanisms involved in the SoB-dependent hepatic protection using a mouse model of fructose-induced NAFLD and in in vitro models. C57BL/6J mice were either pair-fed a fructose-enriched liquid diet ±0·6 g/kg body weight per d SoB or standard chow for 6 weeks. Markers of liver damage, intestinal barrier function, glucose metabolism, toll-like receptor-4 (TLR-4) and melatonin signalling were determined in mice. Differentiated human carcinoma colon-2 (Caco-2) and J774A.1 cells were used to determine molecular mechanisms involved in the effects of SoB. Despite having no effects on markers of intestinal barrier function and glucose metabolism or body weight gain, SoB supplementation significantly attenuated fructose-induced hepatic TAG accumulation and inflammation. The protective effects of SoB were associated with significantly lower expression of markers of the TLR-4-dependent signalling cascade, concentrations of inducible nitric oxide synthase (iNOS) protein and 4-hydroxynonenal protein adducts in liver. Treatment with SoB increased melatonin levels and expression of enzymes involved in melatonin synthesis in duodenal tissue and Caco-2 cells. Moreover, treatment with melatonin significantly attenuated lipopolysaccharide-induced expression of iNOS and nitrate levels in J774A.1 cells. Taken together, our results indicated that the protective effects of SoB on the development of fructose-induced NAFLD in mice are associated with an increased duodenal melatonin synthesis and attenuation of iNOS induction in liver.
RESUMEN
Overnutrition, insulin resistance and an impaired intestinal barrier function are discussed as critical factors in the development of non-alcoholic fatty liver disease. Not only butyrate-producing probiotics as well as supplementation of sodium butyrate (SoB) have been suggested to bear protective effects on liver damage of various aetiologies. However, whether an oral consumption of SoB has a protective effect on Western-style diet (WSD)-induced non-alcoholic steatohepatitis (NASH) and if so molecular mechanism involved has not yet been determined. Eight-week-old C57BL/6J mice were pair-fed either a liquid control or WSD±0·6 g/kg body weight SoB. After 6 weeks, markers of liver damage, inflammation, toll-like receptor (TLR)-4 signalling, lipid peroxidation and glucose as well as lipid metabolism were determined in the liver tissue. Tight junction protein levels were determined in the duodenal tissue. SoB supplementation had no effects on the body weight gain or liver weight of WSD-fed mice, whereas liver steatosis and hepatic inflammation were significantly decreased (e.g. less inflammatory foci and neutrophils) when compared with mice fed only a WSD. Tight junction protein levels in duodenum, hepatic mRNA expression of TLR-4 and sterol regulatory element-binding protein 1c were altered similarly in both WSD groups when compared with controls, whereas protein levels of myeloid differentiation primary response gene 88, inducible nitric oxide synthase, 4-hydroxynonenal protein adducts and F4/80 macrophages were only significantly induced in livers of mice fed only the WSD. In summary, these data suggest that an oral supplementation of SoB protects mice from inflammation in the liver and thus from the development of WSD-induced NASH.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Ácido Butírico/uso terapéutico , Suplementos Dietéticos , Duodeno/inmunología , Mucosa Intestinal/inmunología , Hígado/inmunología , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Animales , Biomarcadores/metabolismo , Dieta Occidental/efectos adversos , Duodeno/metabolismo , Duodeno/patología , Femenino , Fármacos Gastrointestinales/uso terapéutico , Regulación de la Expresión Génica , Inmunohistoquímica , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Peroxidación de Lípido , Hígado/metabolismo , Hígado/patología , Ratones Endogámicos C57BL , Infiltración Neutrófila , Enfermedad del Hígado Graso no Alcohólico/inmunología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Transducción de Señal , Proteínas de Uniones Estrechas/genética , Proteínas de Uniones Estrechas/metabolismo , Receptor Toll-Like 4/antagonistas & inhibidores , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismoRESUMEN
AIM: To determine the prevalence of metabolic abnormalities, and differences between the sexes, in prepubertal overweight and normal weight children aged from 5 to 8 years, without any signs of health impairments or metabolic disturbances at the time of recruitment. METHODS: General health status and inflammatory markers were assessed in 100 overweight and 51 normal weight children, who were living in Germany and had undergone mandatory medical examinations. The study comprised of 81 girls and 70 boys. RESULTS: Despite being recruited as healthy, 73% of the overweight children and 16% of the normal weight children were found to suffer from one or more metabolic abnormalities, such as hypertension or insulin resistance. Girls with a body mass index (BMI) percentile of ≥80th showed an increased susceptibility to metabolic disorders, and a similar effect was found for boys with a BMI percentile of ≥95th. Plasma levels of proinflammatory markers, such as plasminogen activator inhibitor-1 and leptin, were also significantly higher in overweight than normal weight children. CONCLUSION: Metabolic and cardiovascular abnormalities and pro-inflammatory markers were prevalent in overweight prepubertal children. The prevalence rates appeared to differ between the sexes.
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Enfermedades Metabólicas/epidemiología , Niño , Preescolar , Femenino , Humanos , Masculino , Enfermedades Metabólicas/complicaciones , Sobrepeso/complicaciones , Prevalencia , Factores SexualesRESUMEN
The addition of plant oils such as soybean oil (S) to a diet rich in saturated fatty acids is discussed as a possible route to prevent or diminish the development of metabolic disease. Here, we assessed whether a butterfat-rich diet fortified with S affects the development of early non-alcoholic steatohepatitis (NASH) and glucose intolerance. Female C57BL/6J mice were fed a standard-control diet (C); a fat-, fructose-, and cholesterol-rich diet (FFC, 25E% butterfat, 50% (wt./wt.) fructose, 0.16% (wt./wt.) cholesterol); or FFC supplemented with S (FFC + S, 21E% butterfat + 4E% S) for 13 weeks. Indicators of liver damage, inflammation, intestinal barrier function, and glucose metabolism were measured. Lipopolysaccharide (LPS)-challenged J774A.1 cells were incubated with linolenic and linoleic acids (ratio 1:7.1, equivalent to S). The development of early NASH and glucose intolerance was significantly attenuated in FFC + S-fed mice compared to FFC-fed mice associated with lower hepatic toll-like receptor-4 mRNA expression, while markers of intestinal barrier function were significantly higher than in C-fed mice. Linolenic and linoleic acid significantly attenuated LPS-induced formation of reactive nitrogen species and interleukin-1 beta mRNA expression in J774A.1 cells. Our results indicate that fortifying butterfat with S may attenuate the development of NASH and glucose intolerance in mice.
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Mantequilla/efectos adversos , Alimentos Fortificados , Intolerancia a la Glucosa/prevención & control , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Aceite de Soja/uso terapéutico , Animales , Arginasa/metabolismo , Western Blotting , Grasas de la Dieta/efectos adversos , Endotoxinas/sangre , Ácidos Grasos no Esterificados/sangre , Femenino , Intolerancia a la Glucosa/etiología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/patología , PPAR gamma/sangre , Peroxidasa/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Aceite de Soja/administración & dosificación , Factor de Necrosis Tumoral alfa/sangreRESUMEN
BACKGROUND: Absolute dietary fat intake but even more so fatty acid pattern is discussed to be critical in the development of non-alcoholic fatty liver disease (NAFLD). Here, we determined if switching a butterfat enriched diet to a rapeseed oil (RO) enriched diet affects progression of an existing NAFLD and glucose intolerance in mice. METHODS: For eight weeks, female C57Bl/6J mice were either fed a liquid control (C) or a butterfat-, fructose- and cholesterol-rich diet (BFC, 25E% butterfat) to induce early signs of steatohepatitis and glucose intolerance in mice. For additional five weeks mice received either BFC or C or a fat-, fructose- and cholesterol-rich and control diet, in which butterfat was replaced with RO (ROFC and CRO). Markers of glucose metabolism, liver damage and intestinal barrier were assessed. RESULTS: Exchanging butterfat with RO attenuated the progression of BFC diet-induced NAFLD and glucose intolerance. Beneficial effects of RO were associated with lower portal endotoxin levels and an attenuation of the induction of the toll-like receptor-4-dependent signaling cascades in liver. Peroxisome proliferator-activated receptor γ activity was induced in small intestine of ROFC-fed mice. CONCLUSION: Taken together, exchanging butterfat with RO attenuated the progression of diet-induced steatohepatitis and glucose intolerance in mice.
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Mantequilla/efectos adversos , Dieta Alta en Grasa/efectos adversos , Intolerancia a la Glucosa/prevención & control , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Aceite de Brassica napus/uso terapéutico , Animales , Progresión de la Enfermedad , Endotoxinas/metabolismo , Femenino , Riñón/química , Ratones , Ratones Endogámicos C57BL , Receptor Toll-Like 4RESUMEN
Dietary fat is discussed to be critical in the development of non-alcoholic fatty liver disease. Here, we assess the effect of exchanging dietary fat source from butterfat to extra virgin olive oil on the progression of an already existing diet-induced non-alcoholic fatty liver disease in mice. Female C57BL/6J mice were fed a liquid butterfat-, fructose- and cholesterol-rich diet (BFC, 25E% from butterfat) or control diet (C, 12%E from soybean oil) for 13 weeks. In week 9, fat sources of some BFC- and C-fed mice were switched either to 25E% or 12E% olive oil (OFC and CO). Glucose and insulin tolerance tests were performed, and markers of liver damage and glucose metabolism were assessed. After 6 weeks of feeding, BFC-fed mice had developed marked signs of insulin resistance, which progressed to week 12 being not affected by the exchange of fat sources. Liver damage was similar between BFC- and OFC-fed mice. Markers of lipid metabolism and lipid peroxidation in liver and of insulin signaling in liver and muscle were also similarly altered in BFC- and OFC-fed mice. Taken together, our data suggest that exchanging butterfat with extra virgin olive oil has no effect on the progression of non-alcoholic fatty liver disease and glucose tolerance in mice.
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Resistencia a la Insulina , Hígado/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/patología , Aceite de Oliva/farmacología , Animales , Peso Corporal/efectos de los fármacos , Dieta Alta en Grasa , Progresión de la Enfermedad , Femenino , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Insulina/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/veterinaria , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND & AIMS: Recent studies have shown that patients with manifest non-alcoholic fatty liver disease (NAFLD), e.g. steatosis grade 3 or steatohepatitis with or without beginning fibrosis frequently show altered fecal microbiota composition and elevated bacterial endotoxin levels. However, if these alterations are signs of a progressing disease or are already found in initial disease stages has not yet been clarified. METHODS: Twenty children with simple steatosis (grade 1) diagnosed by ultrasound and 29 normal weight healthy control children (age <10 years) were included in the study (mean age 7.6 ± 1.1 years). Metabolic parameters, markers of intestinal barrier function and inflammation were determined. RESULTS: Activity of alanine aminotransferase, concentrations of some markers of inflammation and insulin resistance were significantly higher in plasma of NAFLD children than in controls. When compared to controls, plasma bacterial endotoxin and lipopolysaccharide-binding protein (LBP) levels were significantly higher in NAFLD children (+50% and +24%, respectively), while soluble CD14 serum and D-lactate plasma levels as well as the prevalence of small intestinal bacterial overgrowth did not differ between groups. Plasma endotoxin and LBP levels were positive associated with proinflammatory markers like plasminogen activator inhibitor-1, c-reactive protein, interleukin-6 and leptin while no associations with markers of insulin resistance were found. CONCLUSIONS: Taken together, our results indicate that even in juvenile patients with early stages of NAFLD e.g. simple steatosis grade 1, plasma endotoxin concentrations are already elevated further suggesting that intestinal barrier dysfunction might be present already in the initial phases of the disease.
Asunto(s)
Enfermedad del Hígado Graso no Alcohólico/sangre , Proteínas de Fase Aguda , Adolescente , Alanina Transaminasa/sangre , Proteínas Portadoras/sangre , Niño , Endotoxinas/sangre , Hígado Graso/sangre , Hígado Graso/inmunología , Femenino , Humanos , Inflamación/sangre , Inflamación/inmunología , Resistencia a la Insulina/inmunología , Ácido Láctico/sangre , Receptores de Lipopolisacáridos/sangre , Masculino , Glicoproteínas de Membrana/sangre , Enfermedad del Hígado Graso no Alcohólico/inmunologíaRESUMEN
Intestinal microbiota and barrier functions seem to play an important role in the development of non-alcoholic fatty liver disease (NAFLD). However, whether these changes are an early event in the development of NAFLD or are primarily associated with later stages of the disease, has not yet been clarified. Using a pair-feeding model, we determined the effects of a short-term intake of a fat-, fructose- and cholesterol-rich diet (FFC) on the development of early hepatic steatosis and markers of intestinal barrier function in mice treated with and without non-resorbable antibiotics (AB). For four days, C57BL/6J mice were either pair-fed a control diet or a FFC diet ± AB (92 mg/kg body weight (BW) polymyxin B and 216 mg/kg BW neomycin). Hepatic steatosis and markers of inflammation, lipidperoxidation and intestinal barrier function were assessed. Lipid accumulation and early signs of inflammation found in the livers of FFC-fed mice were markedly attenuated in FFC + AB-fed animals. In FFC-fed mice the development of NAFLD was associated with a significant loss of tight junction proteins and an induction of matrix metalloproteinase-13 in the upper parts of the small intestine as well as significantly higher portal endotoxin levels and an induction of dependent signaling cascades in the liver. As expected, portal endotoxin levels and the expression of dependent signaling cascades in liver tissue were almost at the level of controls in FFC + AB-fed mice. However, FFC + AB-fed mice were also protected from the loss of zonula occludens-1 and partially of occludin protein in small intestine. Our data suggest that the development of early diet-induced hepatic steatosis in mice at least in part results from alterations of intestinal barrier function.
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Antibacterianos/farmacología , Colesterol en la Dieta/efectos adversos , Grasas de la Dieta/efectos adversos , Hígado Graso/tratamiento farmacológico , Fructosa/efectos adversos , Animales , Biomarcadores/metabolismo , Colesterol en la Dieta/administración & dosificación , Dieta/efectos adversos , Grasas de la Dieta/administración & dosificación , Modelos Animales de Enfermedad , Endotoxinas/metabolismo , Hígado Graso/inducido químicamente , Femenino , Fructosa/administración & dosificación , Microbioma Gastrointestinal/efectos de los fármacos , Intestino Delgado/metabolismo , Intestino Delgado/microbiología , Peroxidación de Lípido , Lipogénesis , Metaloproteinasa 13 de la Matriz/genética , Metaloproteinasa 13 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ocludina/genética , Ocludina/metabolismo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Triglicéridos/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismo , Proteína de la Zonula Occludens-1/genética , Proteína de la Zonula Occludens-1/metabolismoRESUMEN
SCOPE: The role of invariant natural killer T cells in the development of nonalcoholic steatohepatitis (NASH) has not yet been fully understood. Here, the effect of the invariant natural killer T-cell activator alpha-galactosylceramide (αGalCer) on the development of nonalcoholic fatty liver disease and intestinal barrier function was assessed in a mouse model of early Western-style diet (WSD) induced NASH. METHODS AND RESULTS: Female C57BL/6J mice were either fed a liquid control diet or a liquid fructose-enriched WSD for 6 wk while being treated three times weekly with αGalCer (2 µg intraperitoneal) or vehicle. Indices of liver damage, glucose metabolism, and intestinal permeability were measured. Treatment with αGalCer markedly suppressed hepatic fat accumulation and inflammation while not affecting fasting glucose. The protective effects of αGalCer were associated with a protection against the increased translocation of bacterial endotoxins and the decreased protein levels of tight junction proteins occludin and zonula occludens 1 found in vehicle-treated mice while being fed a WSD. CONCLUSION: Taken together, our data suggest that the protective effects of αGalCer against the development of a diet-induced NASH in mice are associated with a protection against the increased translocation of intestinal bacterial endotoxins associated with the development of NASH.
Asunto(s)
Galactosilceramidas/farmacología , Intestinos/fisiología , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Sustancias Protectoras/farmacología , Actinas/genética , Actinas/metabolismo , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Dieta Occidental/efectos adversos , Modelos Animales de Enfermedad , Endotoxinas/toxicidad , Femenino , Interferón gamma/metabolismo , Intestinos/microbiología , Ratones , Ratones Endogámicos C57BL , Células T Asesinas Naturales , Enfermedad del Hígado Graso no Alcohólico/etiología , Ocludina/genética , Ocludina/metabolismo , Proteínas de Uniones Estrechas/genética , Proteínas de Uniones Estrechas/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Triglicéridos/sangre , Proteína de la Zonula Occludens-1/genética , Proteína de la Zonula Occludens-1/metabolismoRESUMEN
Introduction. The common adiponutrin (PNPLA3) variant p.Ile148Met is associated with liver injury. Here, we investigate the association of this polymorphism with hepatic and metabolic traits in a pediatric cohort. Patients and Methods. The study cohort comprised 142 German children (age 5-9 years, 98 overweight, 19 children with NAFLD). Results. Overweight children presented with increased serum ALT (P = 0.001) and GGT (P < 0.001) activities. ALT activities differed significantly (P = 0.02) between carriers of different PNPLA3 genotypes in the entire study cohort, in normal weight children (P = 0.02) and in children younger than 7 years (P = 0.02). Carriers of the prosteatotic PNPLA3 genotype p.148Met/Met displayed higher ALT activities as compared to children with the frequent genotype p.148Ile/Ile (P = 0.01). The BMI was however a stronger predictor of ALT activities compared to the PNPLA3 genotype (P < 0.001 and P = 0.06, resp.). The variant was associated with increased serum glucose levels (P = 0.01) and HOMA index (P = 0.02) in carriers of the p.148Ile/Met genotype but did not affect other metabolic traits or the presence of NAFLD. Discussion. The frequent PNPLA3 variant p.Ile148Met is associated with serum ALT activities already at a young age.
RESUMEN
General overnutrition but also a diet rich in certain macronutrients, age, insulin resistance and an impaired intestinal barrier function may be critical factors in the development of nonalcoholic fatty liver disease (NAFLD). Here the effect of chronic intake of diets rich in different macronutrients, i.e. fructose and/or fat on liver status in mice, was studied over time. C57BL/6J mice were fed plain water, 30% fructose solution, a high-fat diet or a combination of both for 8 and 16 weeks. Indices of liver damage, toll-like receptor 4 (TLR-4) signaling cascade, macrophage polarization and insulin resistance in the liver and intestinal barrier function were analyzed. Chronic exposure to a diet rich in fructose and/or fat was associated with the development of hepatic steatosis that progressed with time to steatohepatitis in mice fed a combination of macronutrients. The development of NAFLD was also associated with a marked reduction of the mRNA expression of insulin receptor, whereas hepatic expressions of TLR-4, myeloid differentiation primary response gene 88 and markers of M1 polarization of macrophages were induced in comparison to controls. Bacterial endotoxin levels in portal plasma were found to be increased while levels of the tight junction protein occludin and zonula occludens 1 were found to be significantly lower in the duodenum of all treated groups after 8 and 16 weeks. Our data suggest that chronic intake of fructose and/or fat may lead to the development of NAFLD over time and that this is associated with an increased translocation of bacterial endotoxin.