RESUMO
AIMS/HYPOTHESIS: We examined whether analysis of lipids by ultra-performance liquid chromatography (UPLC) coupled to MS allows the development of a laboratory test for non-alcoholic fatty-liver disease (NAFLD), and how a lipid-profile biomarker compares with the prediction of NAFLD and liver-fat content based on routinely available clinical and laboratory data. METHODS: We analysed the concentrations of molecular lipids by UPLC-MS in blood samples of 679 well-characterised individuals in whom liver-fat content was measured using proton magnetic resonance spectroscopy ((1)H-MRS) or liver biopsy. The participants were divided into biomarker-discovery (n = 287) and validation (n = 392) groups to build and validate the diagnostic models, respectively. RESULTS: Individuals with NAFLD had increased triacylglycerols with low carbon number and double-bond content while lysophosphatidylcholines and ether phospholipids were diminished in those with NAFLD. A serum-lipid signature comprising three molecular lipids ('lipid triplet') was developed to estimate the percentage of liver fat. It had a sensitivity of 69.1% and specificity of 73.8% when applied for diagnosis of NAFLD in the validation series. The usefulness of the lipid triplet was demonstrated in a weight-loss intervention study. CONCLUSIONS/INTERPRETATION: The liver-fat-biomarker signature based on molecular lipids may provide a non-invasive tool to diagnose NAFLD, in addition to highlighting lipid molecular pathways involved in the disease.
Assuntos
Fígado Gorduroso/sangue , Fígado Gorduroso/metabolismo , Lipídeos/sangue , Fígado/metabolismo , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica , Adulto JovemRESUMO
BACKGROUND AND AIM: A recent study in Indian subjects suggested common variants in apolipoprotein C3 (APOC3) (T-455C at rs2854116 and C-482T at rs2854117) to contribute to non-alcoholic fatty liver disease (NAFLD), plasma apoC3 and triglyceride concentrations. Our aim was to determine the contribution of genetic variation in APOC3 on liver fat content and plasma triglyceride and apoC3 concentrations in a larger European cohort. METHODS: A total of 417 Finnish individuals were genotyped for rs2854116 and rs2854117 in APOC3 and the known rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3) influencing liver fat. Plasma apoC3 concentration was measured enzymatically, and liver fat by proton magnetic resonance spectroscopy. RESULTS: APOC3 wild-type homozygotes and variant allele (T-455C or C-482T or both) carriers did not differ with regard to liver fat, apoC3 concentrations, triglyceride-, high density lipoprotein-, fasting plasma glucose, insulin-, alanine aminotransferase- and aspartate aminotransferase-concentrations, nor was there a difference in prevalence of NAFLD. In contrast, carriers of the PNPLA3 GG genotype at rs738409 had a 2.7-fold (median 11.3%) higher liver fat than those with the CC (median 4.2%) genotype. The PNPLA3 rs738409 was also an independent predictor of liver fat, together with age, gender, and body mass index. CONCLUSION: Genetic variants in PNPLA3 but not APOC3 contribute to the variance in liver fat content due to NAFLD.
Assuntos
Apolipoproteína C-III/genética , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Lipase/genética , Proteínas de Membrana/genética , Adulto , Fatores Etários , Alanina Transaminase/sangue , Alelos , Análise de Variância , Apolipoproteína C-III/sangue , Aspartato Aminotransferases/sangue , Glicemia/metabolismo , Índice de Massa Corporal , Feminino , Finlândia , Homozigoto , Humanos , Insulina/sangue , Gordura Intra-Abdominal , Lipoproteínas HDL/sangue , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica , Polimorfismo de Nucleotídeo Único , Fatores Sexuais , Estatísticas não Paramétricas , Triglicerídeos/sangueRESUMO
BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is associated with impaired glucose and lipoprotein metabolism. However, the metabolism of cholesterol in NAFLD remains unexplored. We investigated how fatty liver influences cholesterol metabolism in 242 non-diabetic subjects. METHODS: Liver fat content was measured with proton magnetic resonance spectroscopy. Cholesterol metabolism was assayed with serum non-cholesterol sterols, surrogate markers of cholesterol synthesis and absorption. The analyses were performed with gas-liquid chromatography. RESULTS: A total of 114 subjects had NAFLD and 128 subjects had normal liver fat content. Non-cholesterol sterols reflecting cholesterol synthesis (cholestenol, desmosterol, and lathosterol) were higher, and those reflecting cholesterol absorption (cholestanol and plant sterols) were lower in subjects with NAFLD than in controls, independent of body mass index. Liver fat content was positively associated with markers of cholesterol synthesis (r = from 0.262 to 0.344, p < 0.001 for all) and inversely associated with markers of cholesterol absorption (r = from -0.299 to -0.336, p < 0.001 for all). In the entire study group, synthesis and absorption markers were interrelated, indicating that the homeostasis of cholesterol metabolism was maintained. LDL cholesterol was similar in the two groups. CONCLUSIONS: We demonstrated that although LDL cholesterol concentrations are unchanged, cholesterol metabolism in NAFLD is characterized by increased synthesis and diminished absorption of cholesterol. These changes are associated with liver fat content independent of body weight.
Assuntos
Colesterol na Dieta/farmacocinética , Colesterol/biossíntese , Adulto , Idoso , Índice de Massa Corporal , Estudos de Casos e Controles , Colesterol/sangue , LDL-Colesterol/metabolismo , Fígado Gorduroso/complicações , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Feminino , Humanos , Insulina/sangue , Absorção Intestinal , Fígado/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica , Obesidade/complicações , Obesidade/metabolismo , Obesidade/patologia , Sitosteroides/sangue , Adulto JovemRESUMO
BACKGROUND & AIMS: Animal studies suggest that endocannabinoids could contribute to the development of nonalcoholic fatty liver disease (NAFLD). In addition, NAFLD has been shown to be associated with multiple changes in lipid concentrations in liver biopsies. There are no data on splanchnic free fatty acid (FFA), glycerol, ketone body, endocannabinoid, and lipid fluxes in vivo in subjects with NAFLD. METHODS: We performed hepatic venous catheterization studies in combination with [(2)H(2)]palmitate infusion in the fasting state and during a low-dose insulin infusion in 9 subjects with various degrees of hepatic steatosis as determined using liver biopsy. Splanchnic balance of endocannabinoids and individual lipids was determined using ultra performance liquid chromatography coupled to mass spectrometry. RESULTS: Concentrations of the endocannabinoid 2-arachidonoylglycerol were higher in arterialized (91 ± 33 µg/L basally) than in hepatic venous (51 ± 19 µg/L; P < .05) plasma. Fasting arterial (r = 0.72; P = .031) and hepatic venous (r = 0.70; P = .037) concentrations of 2-arachidonoylglycerol were related positively to liver fat content. Analysis of fluxes of 85 different triglycerides showed that the fatty liver overproduces saturated triglycerides. In the plasma FFA fraction in the basal state, the relative amounts of palmitoleate and linoleate were lower and those of stearate and oleate were higher in the hepatic vein than in the artery. Absolute concentrations of all nontriglyceride lipids were comparable in arterialized venous plasma and the hepatic vein both in the basal and insulin-stimulated states. CONCLUSIONS: The human fatty liver takes up 2-arachidonoylglycerol and overproduces triacylglycerols containing saturated fatty acids, which might reflect increased de novo lipogenesis.
Assuntos
Moduladores de Receptores de Canabinoides/sangue , Endocanabinoides , Ácidos Graxos não Esterificados/sangue , Circulação Esplâncnica/fisiologia , Triglicerídeos/sangue , Ácido 3-Hidroxibutírico/sangue , Cateterismo/métodos , Deutério , Fígado Gorduroso/metabolismo , Fígado Gorduroso/fisiopatologia , Feminino , Glicerol/sangue , Artéria Hepática/fisiologia , Veias Hepáticas/fisiologia , Humanos , Hiperinsulinismo/metabolismo , Hiperinsulinismo/fisiopatologia , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Corpos Cetônicos/sangue , Lipogênese/fisiologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica , Palmitatos/farmacocinéticaRESUMO
BACKGROUND AND AIMS: Obesity and the metabolic syndrome are established risk factors of venous thromboembolism. As most coagulation factors are produced exclusively by the liver and non-alcoholic fatty liver disease (NAFLD) is tightly related to metabolic disorders, we aimed at studying the association of liver fat with various coagulation factor activities. METHODS: Plasma prothrombin (PT) and activated partial thromboplastin time, activities of vWF:RCo, FVII, FVIII, FIX, FXI, FXII, FXIII, fibrinogen and D-dimer concentrations were measured in 54 subjects with and 44 without NAFLD diagnosed by proton magnetic resonance spectroscopy. Subjects were recruited retrospectively for metabolic studies in our laboratory. The body composition and features of insulin resistance were measured in all subjects. RESULTS: FVIII (107±30 vs. 84±22%, P<0.001), FIX (110±14 vs. 94±16%, P<0.001), FXI (109±16 vs. 96±19%, P=0.001) and FXII (113±21 vs. 99±32%, P=0.002) activities were consistently elevated in subjects with as compared with those without NAFLD. Liver fat percentage was positively related to FVIII (r=0.28, P=0.005), FIX (r=0.36, P=0.0003), FXI (r=0.29, P=0.004) and FXII (r=0.30, P=0.003) activities, again independent of age, gender and body mass index (BMI). PT%, vWF:RCo activity and fibrinogen were higher in subjects with as compared with those without NAFLD, but this difference disappeared after adjusting for age, gender and BMI. CONCLUSION: FVIII, FIX, FXI and FXII activities are increased in human NAFLD and correlate with the features of insulin resistance. The relationships between NAFLD and these coagulation factors are independent of age, gender and BMI, suggesting that the fatty liver can contribute to the risk of thrombosis.
Assuntos
Fator IX/metabolismo , Fator VIII/metabolismo , Fator XII/metabolismo , Fator XI/metabolismo , Adulto , Fatores Etários , Idoso , Índice de Massa Corporal , Fígado Gorduroso/sangue , Fígado Gorduroso/metabolismo , Feminino , Fibrinogênio/metabolismo , Finlândia , Humanos , Resistência à Insulina/fisiologia , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica , Tempo de Tromboplastina Parcial , Protrombina/metabolismo , Fatores Sexuais , Fator de von Willebrand/metabolismoRESUMO
BACKGROUND: The aim of this work was to examine the prevalence of different metabolical phenotypes of obesity, and to analyze, by using different risk scores, how the metabolic syndrome (MetS) definition discriminates between unhealthy and healthy metabolic phenotypes in different obesity classes. METHODS: The Finnish type 2 diabetes (FIN-D2D) survey, a part of the larger implementation study, was carried out in 2007. The present cross-sectional analysis comprises 2,849 individuals aged 45-74 years. The MetS was defined with the new Harmonization definition. Cardiovascular risk was estimated with the Framingham and SCORE risk scores. Diabetes risk was assessed with the FINDRISK score. Non-alcoholic fatty liver disease (NAFLD) was estimated with the NAFLD score. Participants with and without MetS were classified in different weight categories and analysis of regression models were used to test the linear trend between body mass index (BMI) and various characteristics in individuals with and without MetS; and interaction between BMI and MetS. RESULTS: A metabolically healthy but obese phenotype was observed in 9.2% of obese men and in 16.4% of obese women. The MetS-BMI interaction was significant for fasting glucose, 2-hour plasma glucose, fasting plasma insulin and insulin resistance (HOMA-IR)(p < 0.001 for all). The prevalence of total diabetes (detected prior to or during survey) was 37.0% in obese individuals with MetS and 4.3% in obese individuals without MetS (p < 0.001). MetS-BMI interaction was significant (p < 0.001) also for the Framingham 10 year CVD risk score, NAFLD score and estimated liver fat %, indicating greater effect of increasing BMI in participants with MetS compared to participants without MetS. The metabolically healthy but obese individuals had lower 2-hour postload glucose levels (p = 0.0030), lower NAFLD scores (p < 0.001) and lower CVD risk scores (Framingham, p < 0.001; SCORE, p = 0.002) than normal weight individuals with MetS. CONCLUSIONS: Undetected Type 2 diabetes was more prevalent among those with MetS irrespective of the BMI class and increasing BMI had a significantly greater effect on estimates of liver fat and future CVD risk among those with MetS compared with participants without MetS. A healthy obese phenotype was associated with a better metabolic profile than observed in normal weight individuals with MetS.
Assuntos
Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Fígado Gorduroso/epidemiologia , Síndrome Metabólica/epidemiologia , Obesidade/epidemiologia , Idoso , Índice de Massa Corporal , Estudos Transversais , Feminino , Finlândia/epidemiologia , Inquéritos Epidemiológicos , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica , Fenótipo , Prevalência , Fatores de RiscoRESUMO
PURPOSE OF REVIEW: Hepatic steatosis is a leading cause of adult and paediatric liver disease and is inextricably linked to obesity, insulin resistance and cardiovascular disease. Here we summarize our current understanding of the role of the patatin-like phospholipase domain-containing 3 gene (PNPLA3) in hepatic steatosis. RECENT FINDINGS: Multiple studies have revealed an association between the common I148M variant in PNPLA3 and increased hepatic fat. In the presence of obesity and chronic alcohol intake, the variant is associated with even more striking phenotypes such as hepatitis and cirrhosis, respectively. These findings suggest that genetic variants in PNPLA3 predispose towards hepatic steatosis and, in the context of other environmental stressors, its progression to irreversible liver failure. PNPLA3 is predominantly expressed in human liver and adipose tissue, possesses both lipolytic and lipogenic activity in vitro and localizes to the surface of lipid droplets in heptocytes. The 148M mutant protein has reduced lipolytic activity, with attendant increased cellular triglyceride accumulation. However, the precise physiological role of PNPLA3 remains mysterious. SUMMARY: Recent studies have implicated PNPLA3 in the pathogenesis of hepatic steatosis. Attempts to describe its function in vivo may provide us with both an opportunity to understand and a strategy to overcome this leading cause of human morbidity.
Assuntos
Fígado Gorduroso/enzimologia , Fígado Gorduroso/etiologia , Fosfolipases A2 Independentes de Cálcio , Animais , Fígado Gorduroso/genética , Regulação Enzimológica da Expressão Gênica , Humanos , Mutação , Fosfolipases A2 Independentes de Cálcio/genética , Fosfolipases A2 Independentes de Cálcio/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
BACKGROUND & AIMS: Our aims were to develop a method to accurately predict non-alcoholic fatty liver disease (NAFLD) and liver fat content based on routinely available clinical and laboratory data and to test whether knowledge of the recently discovered genetic variant in the PNPLA3 gene (rs738409) increases accuracy of the prediction. METHODS: Liver fat content was measured using proton magnetic resonance spectroscopy in 470 subjects, who were randomly divided into estimation (two thirds of the subjects, n = 313) and validation (one third of the subjects, n = 157) groups. Multivariate logistic and linear regression analyses were used to create an NAFLD liver fat score to diagnose NAFLD and liver fat equation to estimate liver fat percentage in each individual. RESULTS: The presence of the metabolic syndrome and type 2 diabetes, fasting serum (fS) insulin, fS-aspartate aminotransferase (AST), and the AST/alanine aminotransferase ratio were independent predictors of NAFLD. The score had an area under the receiver operating characteristic curve of 0.87 in the estimation and 0.86 in the validation group. The optimal cut-off point of -0.640 predicted increased liver fat content with sensitivity of 86% and specificity of 71%. Addition of the genetic information to the score improved the accuracy of the prediction by only <1%. Using the same variables, we developed a liver fat equation from which liver fat percentage of each individual could be estimated. CONCLUSIONS: The NAFLD liver fat score and liver fat equation provide simple and noninvasive tools to predict NAFLD and liver fat content.
Assuntos
Fígado Gorduroso/diagnóstico , Lipase/genética , Lipídeos/análise , Fígado/química , Espectroscopia de Ressonância Magnética , Proteínas de Membrana/genética , Adulto , Diabetes Mellitus Tipo 2/complicações , Fígado Gorduroso/complicações , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Feminino , Genótipo , Humanos , Fígado/patologia , Masculino , Síndrome Metabólica/complicações , Pessoa de Meia-Idade , Modelos Biológicos , Valor Preditivo dos Testes , Curva ROC , Sensibilidade e EspecificidadeRESUMO
PURPOSE: To determine if 3.0-T proton-decoupled phosphorus 31 ((31)P) magnetic resonance (MR) spectroscopy can be used to differentiate between stages of nonalcoholic fatty liver disease (NAFLD) by resolving the components of phosphomonoester (PME) and phosphodiester (PDE) and enabling detection of a greater number of other phosphorus-containing compounds. MATERIALS AND METHODS: This study was approved by the ethics committee of Helsinki University Central Hospital, and written informed consent was obtained from all study subjects. A 3.0-T clinical imager was used to obtain proton-decoupled (31)P MR spectra in the liver of control subjects (n = 12), patients with biopsy-proved simple steatosis due to nonalcoholic causes (nonalcoholic fatty liver, n = 13; nonalcoholic steatohepatitis [NASH], n = 9), and patients with cirrhosis (n = 9) to determine PME, phosphoethanolamine (PE), phosphocholine, PDE, glycerophosphocholine (GPC), glycerophosphoryl ethanolamine, uridine diphosphoglucose, nicotinamide adenine dinucleotide phosphate (NADPH), inorganic phosphate, phosphoenolpyruvate, and alpha-, beta- and gamma-nucleotide triphosphate levels. Liver fat was determined with hydrogen 1 MR spectroscopy. Differences between the disease groups were analyzed with one-way analysis of variance. RESULTS: The PME/(PME + PDE), PME/PDE, and PE/(PME + PDE) ratios were higher and the GPC/(PME + PDE) ratio was lower in patients with cirrhosis than in the other study groups (P < or = .001, one-way analysis of variance). The NADPH/(PME + PDE) ratio was higher in patients with NASH and those with cirrhosis than in control subjects (P < .05, post hoc analyses) and correlated with disease severity (P = .007). CONCLUSION: NADPH, a marker of inflammation and fibrinogenic activity in the liver, is increased in patients with NASH and those with cirrhosis. Proton-decoupled (31)P 3.0-T MR spectroscopy shows promise in the differentiation of NAFLD stages.
Assuntos
Diagnóstico por Computador/métodos , Fígado Gorduroso/metabolismo , Espectroscopia de Ressonância Magnética/métodos , NADP/análise , Adolescente , Adulto , Idoso , Alcoolismo/diagnóstico , Alcoolismo/metabolismo , Biomarcadores/análise , Fígado Gorduroso/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Isótopos de Fósforo/análise , Fótons , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto JovemRESUMO
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is known to be associated with the metabolic syndrome (MetS) and abnormal glucose tolerance. Whether alcoholic fatty liver disease (AFLD) is associated with similar metabolic abnormalities has not been examined in a population-based study. We aimed at assessing the prevalences of NAFLD and AFLD, and to examine to what extent these conditions are associated with MetS and abnormal glucose tolerance. METHODS: The cohort included 2766 Finnish subjects (45-74 years) from the population-based FIN-D2D survey. Features of insulin resistance, components of the MetS, glucose tolerance status by oral glucose tolerance test, serum liver enzyme concentrations, and daily alcohol consumption were assessed. RESULTS: Subjects with NAFLD and AFLD were equally obese and had similar fasting and insulin concentrations. The prevalences of NAFLD and AFLD were 21% (95% CI: 19%-22%) and 7% (95% CI: 6%-8%). The MetS was slightly more prevalent in AFLD (73%) than in NAFLD (70%, p = 0.028), and type 2 diabetes was similarly prevalent in NAFLD and AFLD (24-25%). The MetS and type 2 diabetes were more prevalent in subjects with NAFLD or AFLD compared to subjects with normal LFTs (53% and 14%, p < 0.0001 for both). DISCUSSION AND CONCLUSION: In Finnish middle-aged population, the prevalence of NAFLD is 3-fold higher than that of AFLD. The prevalences of MetS and type 2 diabetes are, however, significantly increased in both NAFLD and AFLD compared to subjects with normal LFTs. Subjects with AFLD are thus similarly metabolically unhealthy as subjects with NAFLD.
Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Fígado Gorduroso/epidemiologia , Síndrome Metabólica/epidemiologia , Adulto , Comorbidade , Fígado Gorduroso/metabolismo , Fígado Gorduroso Alcoólico/epidemiologia , Feminino , Finlândia , Intolerância à Glucose/epidemiologia , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , PrevalênciaRESUMO
BACKGROUND & AIMS: Liver fat is increased in type 2 diabetes. We determined whether it is associated with impaired insulin clearance and to what extent insulin resistance, impaired insulin clearance, or secretion contribute to fasting hyperinsulinemia. We also examined whether insulin suppression of serum free fatty acid (FFA) correlates with liver fat. METHODS: We compared 68 type 2 diabetic patients and age-, gender-, and body mass index (BMI)-matched nondiabetic subjects. Liver fat was determined by (1)H-MRS, body composition by magnetic resonance imaging, and insulin clearance and action on hepatic glucose production (HGP), glucose uptake, and serum FFA by the euglycemic insulin clamp technique (insulin 0.3 mU/kg x min) combined with infusion of [3-(3)H]glucose. RESULTS: Liver fat was 54% higher and insulin clearance 24% lower in type 2 diabetic patients than nondiabetic subjects. The percent suppression of both HGP and serum FFA by insulin were comparable, but serum insulin concentrations were significantly higher (34 mU/L [interquartile range, 30-39 mU/L] vs 25 mU/L [interquartile range, 22-30 mU/L]; P < .0001) in the type 2 diabetic than the nondiabetic subjects. When this difference was taken into account, both hepatic and adipose tissue insulin sensitivity were impaired in the type 2 diabetic subjects. Liver fat correlated with insulin clearance (r = -0.41; P = .001), and hepatic (r = 0.46; P = .0001) and adipose tissue (r = 0.55; P < .0001) insulin sensitivity. Hepatic but not peripheral insulin sensitivity was independently associated with liver fat content. Insulin clearance and secretion were independent determinants of fasting serum insulin. CONCLUSIONS: We conclude that increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance characterize type 2 diabetic patients.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Fígado Gorduroso/metabolismo , Resistência à Insulina , Insulina/sangue , Tecido Adiposo/metabolismo , Adulto , Índice de Massa Corporal , Ácidos Graxos não Esterificados/sangue , Fígado Gorduroso/patologia , Feminino , Técnica Clamp de Glucose , Humanos , Hiperinsulinismo/metabolismo , Fígado/metabolismo , Fígado/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prótons , Análise de RegressãoRESUMO
BACKGROUND: Studies in animals show that changes in hepatic fatty acid oxidation alter liver fat content. Human data regarding whole-body and hepatic lipid oxidation are controversial and based on studies of only a few subjects. AIMS: We examined whether whole-body and hepatic lipid oxidation are altered in subjects with non-alcoholic fatty liver disease (NAFLD) compared with controls. METHODS: In vivo measurements of rates of substrate oxidation and insulin sensitivity (using the euglycaemic hyperinsulinaemic clamp technique in combination with indirect calorimetry and infusion of [3-(3)H]glucose) were performed in subjects with NAFLD [mean liver fat 14.0% (interquartile range 7.5-20.5%), n=29] and in control subjects [1.6% (1.0-3.0%), n=29]. Liver fat was measured using proton magnetic resonance spectroscopy. Plasma concentrations of 3-hydroxybutyrate (3-OHB) were measured as markers of hepatic lipid oxidation. RESULTS: In the basal state, substrate oxidation rates and serum 3-OHB concentrations were comparable in subjects with and without NAFLD. Plasma 3-OHB concentrations were similarly suppressed by insulin in both the groups. During the insulin infusion, whole-body lipid oxidation was inversely correlated with insulin-stimulated glucose disposal (r=-0.48, P<0.0001), which was lower in subjects with NAFLD [3.7+/-0.2 mg/(kg fat-free mass min)] than in the control subjects [5.0+/-0.3 mg/(kg fat-free mass min), P=0.0008]. CONCLUSIONS: Hepatic lipid oxidation is unchanged in NAFLD. Whole-body lipid oxidation is increased because of peripheral insulin resistance. These data imply that alterations in hepatic fatty acid oxidation do not contribute to liver fat content in humans.
Assuntos
Fígado Gorduroso/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo , Ácido 3-Hidroxibutírico/sangue , Adulto , Metabolismo Energético , Ácidos Graxos não Esterificados/metabolismo , Feminino , Humanos , Insulina/farmacologia , Masculino , Pessoa de Meia-Idade , OxirreduçãoRESUMO
Although the epidemic of obesity has been accompanied by an increase in the prevalence of the metabolic syndrome, not all obese develop the syndrome and even lean individuals can be insulin resistant. Both lean and obese insulin resistant individuals have an excess of fat in the liver which is not attributable to alcohol or other known causes of liver disease, a condition defined as nonalcoholic fatty liver disease (NAFLD) by gastroenterologists. The fatty liver is insulin resistant. Liver fat is highly significantly and linearly correlated with all components of the metabolic syndrome independent of obesity. Overproduction of glucose, VLDL, CRP, and coagulation factors by the fatty liver could contribute to the excess risk of cardiovascular disease associated with the metabolic syndrome and NAFLD. Both of the latter conditions also increase the risk of type 2 diabetes and advanced liver disease. The reason why some deposit fat in the liver whereas others do not is poorly understood. Individuals with a fatty liver are more likely to have excess intraabdominal fat and inflammatory changes in adipose tissue. Intervention studies have shown that liver fat can be decreased by weight loss, PPARgamma agonists, and insulin therapy.
Assuntos
Fígado Gorduroso/fisiopatologia , Síndrome Metabólica/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Fígado Gorduroso/complicações , Feminino , Humanos , Resistência à Insulina/fisiologia , Masculino , Síndrome Metabólica/complicações , Relação Cintura-Quadril/efeitos adversosRESUMO
BACKGROUND: Liver fat is an important determinant of insulin requirements during insulin therapy. Peroxisome proliferator-activated receptor (PPAR)-gamma agonists reduce liver fat. We therefore hypothesized that type 2 diabetic patients using exceptionally high doses of insulin might respond well to addition of a PPARgamma agonist. METHODS: We determined the effect of the PPARgamma agonist rosiglitazone on liver fat and directly measured hepatic insulin sensitivity in 14 patients with type 2 diabetes (aged 51 +/- 3 yr, body mass index 36.7 +/- 1.1 kg/m2), who were poorly controlled (glycosylated hemoglobin A 1c (HbA 1c) 8.9 +/- 0.4%) despite using high doses of insulin (218 +/- 22 IU/d) in combination with metformin. Liver fat content (1H-magnetic resonance spectroscopy), hepatic insulin sensitivity [6 h hyperinsulinemic euglycemic clamp (insulin 0.3 mU/kg.min) combined with [3-3H]glucose], body composition (magnetic resonance imaging), substrate oxidation rates (indirect calorimetry), clinical parameters, and liver enzymes were measured before and after rosiglitazone treatment (8 mg/d) for 8 months. RESULTS: During rosiglitazone, HbA(1c) decreased from 8.9 +/- 0.4% to 7.8 +/- 0.3% (P = 0.007) and insulin requirements from 218 +/- 22 to 129 +/- 20 IU/d (P = 0.002). Liver fat content decreased by 46 +/- 9% from 20 +/- 3% to 11 +/- 3% (P = 0.0002). Hepatic insulin sensitivity, measured from the percent suppression of endogenous glucose production by insulin, increased from -40 +/- 7% to -89 +/- 12% (P = 0.001). The percent change in liver fat correlated with the percent decrease in HbA 1c (r = 0.53, P = 0.06), insulin dose (r = 0.66, P = 0.014), and suppression of endogenous glucose production (r = 0.76, P = 0.003). CONCLUSIONS: Our results suggest that rosiglitazone may be particularly effective in type 2 diabetic patients who are poorly controlled despite using high insulin doses. The mechanism is likely to involve reduced liver fat and enhanced hepatic insulin sensitivity.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina/uso terapêutico , Fígado/metabolismo , PPAR gama/agonistas , Tiazolidinedionas/uso terapêutico , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Glicemia/metabolismo , Composição Corporal , Calorimetria Indireta , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/metabolismo , Metabolismo Energético , Feminino , Técnica Clamp de Glucose , Humanos , Hipoglicemiantes/uso terapêutico , Fígado/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Oxirredução , RosiglitazonaRESUMO
BACKGROUND AND AIMS: The liver is the main source and insulin the main regulator of IGF binding protein 1 (IGFBP-1) in humans. Here we examined how serum IGFBP-1 concentrations are related to directly measured hepatic insulin sensitivity and liver fat content in humans. METHODS: We measured fasting serum (fS) IGFBP-1 concentrations and liver fat content by proton magnetic resonance spectroscopy in 113 nondiabetic subjects. In addition, hepatic insulin sensitivity was measured using the euglycemic hyperinsulinemic clamp (insulin 0.3 mU/kg.min) technique in combination with the infusion of [3-(3)H]glucose in 78 subjects. RESULTS: fS-IGFBP-1 concentrations were inversely related to liver fat content (r = -0.38, P < 0.0001). Of circulating parameters, fS-IGFBP-1 was better correlated to hepatic insulin sensitivity (r = 0.48, P < 0.0001) than fS-insulin (r = -0.42, P = 0.0001), fS-C-peptide (r = -0.41, P = 0.0002), fS-triglyceride (r = -0.33, P = 0.003), or fS-high-density lipoprotein cholesterol (r = 0.30, P = 0.007). In multiple linear regression analyses, body mass index (P < 0.0001) and fS-IGFBP-1 (P = 0.008), but neither age nor gender, were independently associated with hepatic insulin sensitivity (P < 0.0001 for ANOVA). Neither fS-insulin nor fS-C-peptide were independent determinants of hepatic insulin sensitivity after adjusting for age, gender, and body mass index. CONCLUSIONS: fS-IGFBP-1 is inversely correlated with liver fat and is an obesity-independent and liver-specific circulating marker of hepatic insulin sensitivity.
Assuntos
Resistência à Insulina/fisiologia , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fígado/fisiologia , Adolescente , Adulto , Envelhecimento/metabolismo , Biomarcadores , Glicemia/metabolismo , Composição Corporal , Índice de Massa Corporal , Peptídeo C/sangue , Feminino , Humanos , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Insulina/farmacologia , Metabolismo dos Lipídeos , Lipídeos/sangue , Fígado/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Caracteres Sexuais , Circunferência da CinturaRESUMO
BACKGROUND: The liver, once fatty, overproduces components of the metabolic syndrome, such as glucose and lipids. The amount of liver fat in subjects with and without the metabolic syndrome has not been determined. It is unknown which clinically available markers best reflect liver fat content. MEASUREMENTS: Components of the metabolic syndrome as defined by the International Diabetes Federation and liver fat content by proton magnetic resonance spectroscopy were measured in 271 nondiabetic subjects (162 women, 109 men). In addition, other features of insulin resistance (serum insulin, C-peptide), intraabdominal and sc fat by magnetic resonance imaging, and liver enzymes (serum alanine aminotransferase and serum aspartate aminotransferase) were measured. RESULTS: Liver fat was 4-fold higher in subjects with [n = 116; median 8.2% (interquartile range 3.2-18.7%)] than without [n = 155; 2.0% (1.0-5.0%); P < 0.0001] the metabolic syndrome. This increase in liver fat remained significant after adjusting for age, gender, and body mass index. All components of the metabolic syndrome correlated with liver fat content. The best correlate was waist in both women (r = 0.59, P < 0.0001) and men (r = 0.56, P < 0.0001). Liver fat correlated significantly with serum alanine aminotransferase (r = 0.39, P < 0.0001 for women; r = 0.44, P < 0.0001 for men) and aspartate aminotransferase (r = 0.27, P = 0.0005 for women; r = 0.31, P = 0.0012 for men) concentrations. The best correlates of liver fat were fasting serum insulin (r = 0.61; P < 0.0001 for both women and men) and C-peptide (r = 0.62; P < 0.0001 for both women and men). CONCLUSIONS: Liver fat content is significantly increased in subjects with the metabolic syndrome as compared with those without the syndrome, independently of age, gender, and body mass index. Of other markers, serum C-peptide is the strongest correlate of liver fat.
Assuntos
Lipídeos/análise , Fígado/química , Síndrome Metabólica/etiologia , Gordura Abdominal/anatomia & histologia , Adulto , Idoso , Composição Corporal , Peptídeo C/sangue , Feminino , Humanos , Fígado/enzimologia , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/diagnóstico por imagem , Pessoa de Meia-Idade , Radiografia , Caracteres SexuaisRESUMO
Non-alcohol-related fatty liver disease (NAFLD) encompasses a wide spectrum, ranging from steatosis alone to steatohepatitis and fibrosis. Presence of steatohepatitis and fibrosis are key hallmarks of disease progression. Previous studies have demonstrated an association between hepatocyte p21 expression and fibrosis stage in NAFLD. The aim of this study is to investigate the association between the variants of CDKN1A, which encodes p21, and disease progression in NAFLD. To this end, the relation between CDKN1A polymorphism and liver fibrosis was studied in 2 cohorts of biopsy-proven NAFLD patients from UK (n = 323) and Finland (n = 123). Genotyping was performed using DNA isolated from lymphocytes collected at the time of liver biopsy. The findings of the UK cohort were tested in the Finnish cohort. Both the UK and Finnish cohorts were significantly different from each other in basic demographics. In the UK cohort, rs762623, of the 6 SNPs across CDKN1A tested, was significantly associated with disease progression in NAFLD. This association was confirmed in the Finnish cohort. Despite the influence on fibrosis development, SNPs across CDKN1A did not affect the progression of liver fibrosis. In conclusion, CDKN1A variant rs762623 is associated with the development but not the propagation of progressive liver disease in NAFLD.
Assuntos
Senescência Celular , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Estudos de Coortes , Inibidor de Quinase Dependente de Ciclina p21/genética , Progressão da Doença , Inglaterra , Feminino , Finlândia , Estudos de Associação Genética , Humanos , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/patologia , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
PURPOSE: Both non-alcoholic fatty liver (NAFL) and alcoholic fatty liver (AFL) are strongly associated with obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM). Recently, also the vitamin D level has been associated with these and may also be associated with fatty liver (FL). Liver function tests (LFTs) are insensitive markers of FL, but use of scores may help in identifying subjects with FL. We studied how LFTs and the FL score predict the development of T2DM in subjects with AFL versus NAFL and low versus high vitamin D levels. METHODS: A cohort study based on 4,517 participants, aged 40-79, from the representative Mini-Finland Health Survey was carried out. During a follow-up of 15 years, 217 T2DM cases occurred. LFTs were determined from serum samples, and the FL score was formed using BMI, fasting glucose, HDL cholesterol, and GGT concentrations. RESULTS: The risk of T2DM incidence in the highest versus lowest quartile was twofold for the LFTs and ninefold for the FL score. A total of 77 % (95 % confidence interval: 57-87 %) of the T2DM cases could have been prevented if all individuals' FL scores had been at the level of the first quartile. Heavy alcohol consumption and low serum vitamin D concentrations were associated with an increased risk of T2DM among individuals with high FL scores. CONCLUSIONS: The FL score is a useful tool for diagnosing FL in epidemiological studies. A high FL score predicts increased risk of T2DM, especially when combined with heavy alcohol consumption or low vitamin D levels.
RESUMO
BACKGROUND AND AIM: Obesity is associated with elevated serum transaminase levels and non-alcoholic fatty liver disease and weight loss is a recommended therapeutic strategy. Bariatric surgery is effective in obtaining and maintaining weight loss. Aim of the present study was to examine the long-term effects of bariatric surgery on transaminase levels in obese individuals. METHODS: The Swedish Obese Subjects (SOS) study is a prospective controlled intervention study designed to compare the long-term effects of bariatric surgery and usual care in obese subjects. A total of 3,570 obese participants with no excess of alcohol consumption at baseline (1,795 and 1,775 in the control and surgery group, respectively) were included in the analyses. Changes in transaminase levels during follow-up were compared in the surgery and control groups. RESULTS: Compared to usual care, bariatric surgery was associated with lower serum ALT and AST levels at 2- and 10- year follow up. The reduction in ALT levels was proportional to the degree of weight loss. Both the incidence of and the remission from high transaminase levels were more favorable in the surgery group compared to the control group. Similarly, the prevalence of ALT/AST ratio <1 was lower in the surgery compared to the control group at both 2- and 10-year follow up. CONCLUSIONS: Bariatric surgery results in a sustained reduction in transaminase levels and a long-term benefit in obese individuals.
Assuntos
Cirurgia Bariátrica , Fígado/enzimologia , Obesidade/cirurgia , Transaminases/sangue , Adulto , Peso Corporal , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/epidemiologia , Estudos Prospectivos , Suécia/epidemiologia , TempoRESUMO
Coagulation and fibrinolytic activities are under strong genetic control. We studied the effects of acquired obesity, independent of genetic factors on coagulation and fibrinolysis activities in obesity-discordant healthy monozygotic (MZ) twin pairs. Fourteen obesity-discordant (BMI within-pair difference >3 kg/m(2)) and 10 concordant (BMI difference <2 kg/m(2)) MZ twin pairs were identified from the nationwide FinnTwin16 study. Body composition (dual-energy x-ray absorptiometry), abdominal fat distribution (magnetic resonance imaging), liver fat (magnetic resonance spectroscopy), high sensitivity C-reactive protein, insulin sensitivity (euglycemic hyperinsulinemic clamp), and a panel of different markers of blood coagulation and fibrinolysis in the fasting state were measured. Strong resemblance was observed in most coagulation factors within all twin pairs, with the intraclass correlations ranging from 0.73 to 0.97, P < 0.03. However, the activities of fibrinogen and FIX, FXI, and FXII, and plasminogen activator inhibitor-1 (PAI-1) activities were increased in the obese co-twins (P < 0.05) and strongly correlated with the measures of adiposity, inflammation, and insulin resistance (r = 0.32-0.73, P < 0.05) among the twin individuals. Intrapair differences in fibrinogen and PAI-1 correlated with those in BMI, adiposity, and fasting insulin levels (r = 0.40-0.58, P < 0.05) indicating the independent effect of obesity. Derangements of blood coagulation and fibrinolysis are present already in early adulthood in obese subjects. Acquired obesity, independent of genetic factors, increases the activities of fibrinogen and activities of FIX, FXI, FXII, and PAI-1. This study confirms the mechanisms of simultaneous activities of intrinsic coagulation factors and impaired fibrinolysis predisposing obese subjects to thrombosis.