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1.
Nutrients ; 14(12)2022 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-35745158

RESUMO

In cross-sectional studies, the genetic variant rs662799 of the APOA5 gene is associated with high serum triglyceride concentrations, and in some studies, the effect of short-term dietary interventions has been evaluated. The aim of the present investigation was to evaluate the role of this genetic variant in metabolic changes after the consumption of a low-calorie diet with a Mediterranean pattern for 9 months. A population of 269 Caucasian obese patients was recruited. Adiposity and biochemical parameters were measured at the beginning (basal level) and after 3 and 9 months of the dietary intervention. The rs662799 genotype was assessed with a dominant analysis (TT vs. CT + CC). The APOA5 variant distribution was: 88.1% (n = 237) (TT), 11.5% (n = 31) (TC) and 0.4% (n = 1) (CC). There were significant differences only in triglyceride levels at all times of the study between the genotype groups. After 3 and 9 months of dietary intervention, the following parameters improved in both genotype groups: adiposity parameters, systolic pressure, total cholesterol, LDL cholesterol, leptin, adiponectin and the leptin/adiponectin ratio. The intervention significantly decreased insulin levels, HOMA-IR and triglyceride levels in non-C allele carriers (Delta 9 months TT vs. TC + CC). i.e., insulin levels (delta: -3.8 + 0.3 UI/L vs. -1.2 + 0.2 UI/L; p = 0.02), HOMA-IR levels (delta: -1.2 + 0.2 units vs. -0.3 + 0.1 units; p = 0.02), triglyceride levels (delta: -19.3 + 4.2 mg/dL vs. -4.2 + 3.0 mg/dL; p = 0.02). In conclusion, non-C allele carriers of rs662799 of the APOA5 gene showed a decrease of triglyceride, insulin and HOMA-IR levels after consuming a low-calorie diet with a Mediterranean pattern; we did not observe this effect in C allele carriers, despite a significant weight loss.


Assuntos
Restrição Calórica , Resistência à Insulina , Adiponectina/genética , Apolipoproteínas A/genética , Estudos Transversais , Dieta Redutora , Genótipo , Humanos , Insulina , Resistência à Insulina/genética , Leptina , Obesidade , Polimorfismo de Nucleotídeo Único , Triglicerídeos
2.
Liver Int ; 42(8): 1783-1792, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35643936

RESUMO

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) has become a major public health problem, but the prevalence of fibrosis associated with non-alcoholic steatohepatitis (NASH) is largely unknown in the general population. This study aimed to provide an updated estimation of the prevalence of NASH fibrosis in Spain. METHODS: This was an observational, retrospective, cross-sectional, population-based study with merged data from two Spanish datasets: a large (N = 12 246) population-based cohort (ETHON), including transient elastography (TE) data, and a contemporary multi-centric biopsy-proven NASH cohort with paired TE data from tertiary centres (N = 501). Prevalence for each NASH fibrosis stage was estimated by crossing TE data from ETHON dataset with histology data from the biopsy-proven cohort. RESULTS: From the patients with valid TE in ETHON dataset (N = 11 440), 5.61% (95% confidence interval [95% CI]: 2.53-11.97) had a liver stiffness measurement (LSM) ≥ 8 kPa. The proportion attributable to NAFLD (using clinical variables and Controlled Attenuation Parameter) was 57.3% and thus, the estimated prevalence of population with LSM ≥ 8 kPa because of NAFLD was 3.21% (95% CI 1.13-8.75). In the biopsy-proven NASH cohort, 389 patients had LSM ≥ 8 kPa. Among these, 37% did not have significant fibrosis (F2-4). The estimated prevalence of NASH F2-3 and cirrhosis in Spain's adult population were 1.33% (95% CI 0.29-5.98) and 0.70% (95% CI 0.10-4.95) respectively. CONCLUSIONS: These estimations provide an accurate picture of the current prevalence of NASH-related fibrosis in Spain and can serve as reference point for dimensioning the therapeutic efforts that will be required as NASH therapies become available.


Assuntos
Técnicas de Imagem por Elasticidade , Hepatopatia Gordurosa não Alcoólica , Adulto , Estudos Transversais , Fibrose , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/epidemiologia , Cirrose Hepática/etiologia , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Prevalência , Estudos Prospectivos , Estudos Retrospectivos , Espanha/epidemiologia
4.
Sci Rep ; 12(1): 3418, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35232986

RESUMO

The main aim was to evaluate changes in urea cycle enzymes in NAFLD patients and in two preclinical animal models mimicking this entity. Seventeen liver specimens from NAFLD patients were included for immunohistochemistry and gene expression analyses. Three-hundred-and-eighty-two biopsy-proven NAFLD patients were genotyped for rs1047891, a functional variant located in carbamoyl phosphate synthetase-1 (CPS1) gene. Two preclinical models were employed to analyse CPS1 by immunohistochemistry, a choline deficient high-fat diet model (CDA-HFD) and a high fat diet LDLr knockout model (LDLr -/-). A significant downregulation in mRNA was observed in CPS1 and ornithine transcarbamylase (OTC1) in simple steatosis and NASH-fibrosis patients versus controls. Further, age, obesity (BMI > 30 kg/m2), diabetes mellitus and ALT were found to be risk factors whereas A-allele from CPS1 was a protective factor from liver fibrosis. CPS1 hepatic expression was diminished in parallel with the increase of fibrosis, and its levels reverted up to normality after changing diet in CDA-HFD mice. In conclusion, liver fibrosis and steatosis were associated with a reduction in both gene and protein expression patterns of mitochondrial urea cycle enzymes. A-allele from a variant on CPS1 may protect from fibrosis development. CPS1 expression is restored in a preclinical model when the main trigger of the liver damage disappears.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Carbamoil-Fosfato Sintase (Amônia)/genética , Carbamoil-Fosfato Sintase (Amônia)/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Humanos , Fígado/metabolismo , Cirrose Hepática/patologia , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ureia/metabolismo
5.
Dis Markers ; 2022: 6777283, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35295321

RESUMO

Background: The effects of weight loss therapies on omentin-1 levels have been unclear, showing both elevations and decreases in circulating levels. The role of dietary fat might have an important role. The aim of our investigation was to evaluate the influence of weight decrease on omentin-1 levels after two different high-fat hypocaloric diets. Methods: 319 Caucasian obese subjects were randomly allocated during 12 weeks (Diet M (high monounsaturated fat diet) vs. Diet P (high polyunsaturated fat diet)). The mean age was 47.2 ± 5.0 years (range: 26-64), and the mean body mass index (BMI) was 37.9 ± 4.1 kg/m2 (range: 30.6-39.8). Sex distribution was 237 females (74.7%) and 72 males (25.3%). Anthropometric and biochemical parameters were evaluated at basal and after both diets. SPSS 23.0 has been used to realize univariant and multivariant statistical analysis. Results: After both diets, BMI, weight, fat mass, waist circumference, systolic blood, LDL-cholesterol, insulin levels, and HOMA-IR decreased in a statistical way from basal values. These improvements were similar in both diets. After Diet P, omentin-1 levels increase (21.2 ± 9.1 ng/ml: P = 0.02), and after Diet M, this adipokine increases (47.1 ± 11.2 ng/ml: P = 0.02), too. The increase of omentin-1 with Diet M was statistically significantly higher than that after Diet P (P = 0.01). A multiple regression analyses adjusted by age and sex reported a statistical relation between BMI (kg/m2) and insulin (UI/L) with omentin-1 levels. Conclusions: Our study demonstrated a significant improvement on serum omentin-1 levels after weight loss secondary to both diets; in contrast, omentin-1 improvement was higher with Diet M than with Diet P.


Assuntos
Dieta Hiperlipídica , Dieta Redutora , Obesidade/sangue , Obesidade/dietoterapia , Redução de Peso , Adipocinas/metabolismo , Índice de Massa Corporal , Citocinas/sangue , Feminino , Proteínas Ligadas por GPI/sangue , Humanos , Insulina/sangue , Lectinas/sangue , Masculino , Pessoa de Meia-Idade , Obesidade/genética
6.
Crit Care ; 26(1): 4, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35000603

RESUMO

BACKGROUND: Despite growing interest in treatment strategies that limit oxygen exposure in ICU patients, no studies have compared conservative oxygen with standard oxygen in postsurgical patients with sepsis/septic shock, although there are indications that it may improve outcomes. It has been proven that high partial pressure of oxygen in arterial blood (PaO2) reduces the rate of surgical-wound infections and mortality in patients under major surgery. The aim of this study is to examine whether PaO2 is associated with risk of death in adult patients with sepsis/septic shock after major surgery. METHODS: We performed a secondary analysis of a prospective observational study in 454 patients who underwent major surgery admitted into a single ICU. Patients were stratified in two groups whether they had hyperoxemia, defined as PaO2 > 100 mmHg (n = 216), or PaO2 ≤ 100 mmHg (n = 238) at the day of sepsis/septic shock onset according to SEPSIS-3 criteria maintained during 48 h. Primary end-point was 90-day mortality after diagnosis of sepsis. Secondary endpoints were ICU length of stay and time to extubation. RESULTS: In patients with PaO2 ≤ 100 mmHg, we found prolonged mechanical ventilation (2 [8] vs. 1 [4] days, p < 0.001), higher ICU stay (8 [13] vs. 5 [9] days, p < 0.001), higher organ dysfunction as assessed by SOFA score (9 [3] vs. 7 [5], p < 0.001), higher prevalence of septic shock (200/238, 84.0% vs 145/216) 67.1%, p < 0.001), and higher 90-day mortality (37.0% [88] vs. 25.5% [55], p = 0.008). Hyperoxemia was associated with higher probability of 90-day survival in a multivariate analysis (OR 0.61, 95%CI: 0.39-0.95, p = 0.029), independent of age, chronic renal failure, procalcitonin levels, and APACHE II score > 19. These findings were confirmed when patients with severe hypoxemia at the time of study inclusion were excluded. CONCLUSIONS: Oxygenation with a PaO2 above 100 mmHg was independently associated with lower 90-day mortality, shorter ICU stay and intubation time in critically ill postsurgical sepsis/septic shock patients. Our findings open a new venue for designing clinical trials to evaluate the boundaries of PaO2 in postsurgical patients with severe infections.


Assuntos
Sepse , Choque Séptico , Adulto , Humanos , Unidades de Terapia Intensiva , Pró-Calcitonina , Prognóstico , Estudos Prospectivos
7.
Dis Markers ; 2022: 3706753, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35059043

RESUMO

BACKGROUND: Few studies have examined gene expression in peripheral blood mononuclear cells (PBMCs) after a dietary intervention. OBJECTIVE: Our study is aimed at evaluating in a pilot study the peripheral blood gene expression in obese patients after weight loss secondary to a hypocaloric Mediterranean diet. DESIGN: A sample of 11 obese subjects without metabolic syndrome was enrolled. Biochemical, anthropometric parameters and microarray analysis were performed at baseline and after 6 months of dietary intervention. RESULTS: The mean age was 43.1 ± 6.3 years, and the mean body mass index (BMI) was 38.6 ± 8.1 kg/m2. All the next improvements were statistically significant: body weight -7.4 ± 1.9 kg, BMI -2.5 ± 0.2 kg, fat mass -5.7 ± 1.2 kg, waist circumference -5.8 ± 1.2 cm, triglycerides -17.4 ± 6.5 mg/dl, C-reactive protein -3.1 ± 1.5 mg/dL, insulin -2.1 ± 1.0 mUI/L, and HOMA-IR -0.7 ± 0.2 units. We identified 634 differentially expressed genes: 262 genes with relative higher expression levels and 372 with lower expression levels. Cluster analysis showed 35 genes in nutritional disease and 17 genes in endocrine system. The most relevant gene was thyroid peroxidase (TPO), and this gene was overexpressed, and the next genes carbonic anhydrase VI (CA6), caveolin protein 1 (CAV1) and solute carrier family type 12 (SLLC12A3), soluble carrier family type 12 (SLLC12A3), beta 3 receptor (ADRB3), and glutamate receptor ionotropic N methyl D aspartate 2 A (GRIN2A) were all underexpressed. CONCLUSION: In PBMC from obese patients after a diet with a Mediterranean pattern, the expression of 634 genes, of the endocrine system and of nutritional disease, is modified.


Assuntos
Dieta Mediterrânea , Dieta Redutora , Leucócitos Mononucleares , Obesidade , Adulto , Expressão Gênica , Humanos , Pessoa de Meia-Idade , Obesidade/dietoterapia , Projetos Piloto , Receptores Adrenérgicos beta 3
8.
Gut ; 71(2): 382-390, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-33541866

RESUMO

OBJECTIVE: The full phenotypic expression of non-alcoholic fatty liver disease (NAFLD) in lean subjects is incompletely characterised. We aimed to investigate prevalence, characteristics and long-term prognosis of Caucasian lean subjects with NAFLD. DESIGN: The study cohort comprises 1339 biopsy-proven NAFLD subjects from four countries (Italy, UK, Spain and Australia), stratified into lean and non-lean (body mass index (BMI) 10 483 person-years), 4.7% of lean vs 7.7% of non-lean patients reported liver-related events (p=0.37). No difference in survival was observed compared with non-lean NAFLD (p=0.069). CONCLUSIONS: Caucasian lean subjects with NAFLD may progress to advanced liver disease, develop metabolic comorbidities and experience cardiovascular disease (CVD) as well as liver-related mortality, independent of longitudinal progression to obesity and PNPLA3 genotype. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD where the disease manifests at lower overall BMI thresholds. LAY SUMMARY: NAFLD may affect and progress in both obese and lean individuals. Lean subjects are predominantly males, have a younger age at diagnosis and are more prevalent in some geographic areas. During the follow-up, lean subjects can develop hepatic and extrahepatic disease, including metabolic comorbidities, in the absence of weight gain. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD.


Assuntos
Hepatopatia Gordurosa não Alcoólica/complicações , Magreza/complicações , Adulto , Índice de Massa Corporal , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/mortalidade , Hepatopatia Gordurosa não Alcoólica/patologia , Prognóstico , Taxa de Sobrevida , Magreza/mortalidade , Magreza/patologia
9.
J Hum Nutr Diet ; 35(4): 722-730, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34907604

RESUMO

BACKGROUND: The single nucleotide polymorphism (SNP) (rs10401670) of the RETN gene has been associated with metabolic disorder in obese subjects and has scarcely been evaluated after dietary interventions. The present study aimed to analyse the effects of the rs10401670 RETN gene polymorphism on metabolic changes secondary to weight loss and secondary to a high-fat hypocaloric diet with a Mediterranean dietary pattern. METHODS: A Caucasian population comprising 284 obese patients without diabetes mellitus was analysed. Before and after 3 months of a high-fat hypocaloric diet with a Mediterranean pattern, an anthropometric evaluation, an assessment of nutritional intake and a biochemical analysis were performed. A statistical analysis was conducted for the combined CT and TT as a group and for wild-type CC as a second group. RESULTS: Decreases in weight, body mass index (BMI), fat mass, systolic blood pressure and waist circumference were similar in both genotypes groups. In T allele carriers, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), triglycerides and C-reactive protein levels were decreased. The decrease in these parameters was statistically significant for triglycerides (-22.3 ± 9.3 mg dl-1 : p = 0.03), C-reactive protein (-2.8 ± 0.5 mg dl-1 : p = 0.03), insulin (-7.4 ± 2.9 mUI L-1 : p = 0.03) and HOMA-IR (-2.4 ± 1.0: p = 0.02). Leptin levels were decreased in both genotypes groups after the hypocaloric diet, as well as the anthropometric parameters BMI, weight, waist circumference and fat mass. Resistin and adiponectin levels remained unchanged in both groups. CONCLUSIONS: In the present study, we have detected a significant association between the T allele of this SNP and a better response of insulin resistance, triglycerides and C-reactive protein compared to non T allele carriers after weight loss with a high-fat hypocaloric diet and a Mediterranean diet.


Assuntos
Dieta Redutora , Resistência à Insulina , Obesidade , Resistina , Redução de Peso , Proteína C-Reativa , Dieta Hiperlipídica , Humanos , Insulina , Resistência à Insulina/genética , Obesidade/dietoterapia , Obesidade/genética , Resistina/genética , Triglicerídeos , Redução de Peso/genética
10.
Redox Biol ; 48: 102181, 2021 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-34768063

RESUMO

BACKGROUND: Oxidative stress may be a key player in COVID-19 pathogenesis due to its significant role in response to infections. A defective redox balance has been related to viral pathogenesis developing a massive induction of cell death provoked by oxidative stress. The aim of this study is to perform a complete oxidative stress profile evaluation regarding antioxidant enzymes, total antioxidant capacity and oxidative cell damage in order to characterize its role in diagnosis and severity of this disease. METHODS: Blood samples were obtained from 108 COVID-19 patients and 28 controls and metabolites representative of oxidative stress were assessed. The association between lipid peroxidation and 28-day intubation/death risk was evaluated by multivariable regression analysis. Probability of intubation/death to day-28 was analyzed by using Kaplan-Meier curves and tested with the log-rank test. RESULTS: Antioxidant enzymes (Superoxide dismutase (SOD) and Catalase) and oxidative cell damage (Carbonyl and Lipid peroxidation (LPO)) levels were significantly higher in COVID-19 patients while total antioxidant capacity (ABTS and FRAP) levels were lower in these patients. The comparison of oxidative stress molecules' levels across COVID-19 severity revealed that only LPO was statistically different between mild and intubated/death COVID-19 patients. COX multivariate regression analysis identified LPO levels over the OOP (LPO>1948.17 µM) as an independent risk factor for 28-day intubation/death in COVID-19 patients [OR: 2.57; 95% CI: 1.10-5.99; p = 0.029]. Furthermore, Kaplan-Meier curve analysis revealed that COVID-19 patients showing LPO levels above 1948.17 µM were intubated or died 8.4 days earlier on average (mean survival time 15.4 vs 23.8 days) when assessing 28-day intubation/death risk (p < 0.001). CONCLUSION: These findings deepen our knowledge of oxidative stress status in SARS-CoV-2 infection, supporting its important role in COVID-19. In fact, higher lipid peroxidation levels are independently associated to a higher risk of intubation or death at 28 days in COVID-19 patients.

11.
J Pers Med ; 11(7)2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34357148

RESUMO

Antigen tests or polymerase chain reaction (PCR) amplification are currently COVID-19 diagnostic tools. However, developing complementary diagnosis tools is mandatory. Thus, we performed a plasma cytokine array in COVID-19 patients to identify novel diagnostic biomarkers. A discovery-validation study in two independent prospective cohorts was performed. The discovery cohort included 136 COVID-19 and non-COVID-19 patients recruited consecutively from 24 March to 11 April 2020. Forty-five cytokines' quantification by the MAGPIX system (Luminex Corp., Austin, TX, USA) was performed in plasma samples. The validation cohort included 117 patients recruited consecutively from 15 to 25 April 2020 for validating results by ELISA. COVID-19 patients showed different levels of multiple cytokines compared to non-COVID-19 patients. A single chemokine, IP-10, accurately identified COVID-19 patients who required hospital admission (AUC: 0.962; 95%CI (0.933-0.992); p < 0.001)). The results were validated in an independent cohort by multivariable analysis (OR: 25.573; 95%CI (8.127-80.469); p < 0.001) and AUROC (AUC: 0.900; 95%CI (0.846-0.954); p < 0.001). Moreover, showing IP-10 plasma levels over 173.35 pg/mL identified COVID-19 with higher sensitivity (86.20%) than the first SARS-CoV-2 PCR. Our discover-validation study identified IP-10 as a robust biomarker in clinical practice for COVID-19 diagnosis at hospital. Therefore, IP-10 could be used as a complementary tool in clinical practice, especially in emergency departments.

12.
Ann Nutr Metab ; 77(5): 299-306, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34350864

RESUMO

BACKGROUND AND AIMS: This ApoA5-1131C allele of rs662799 variant is related with a higher serum triglyceride levels, and it contributes to increase risk of cardiovascular disease. The aim of the present investigation was to evaluate single nucleotide polymorphism rs662799 in APOA5 gene and its associations with cardiovascular risk factors, MS, and serum adipokine levels. METHODS: The study involved a population of 1,002 Caucasian obese subjects. Measurements of body weight, waist circumference, fat mass, arterial blood pressure, blood glucose, C-reactive protein, insulin levels, insulin resistance (HOMA-IR), lipid profile, and adipokines levels were recorded. Genotype of ApoA5 gene polymorphism (rs662799) and prevalence of metabolic syndrome (MS) were evaluated. RESULTS: The distribution of the rs662799 polymorphism in this adult population (n = 1,002) was 88.3% (n = 885) (TT), 11.4% (n = 114) (TC), and 0.3% (n = 3) (CC). No significant differences were found between the 2 genotypes in the anthropometric data, MS, or blood pressure. Triglyceride levels were higher in C-allele carriers (delta total group: 19.7 ± 2.1 mg/dL: p = 0.02) than non C-allele carriers. HDL-cholesterol levels were lower in C-allele carriers (delta total group: -6.7 ± 1.1 mg/dL: p = 0.02) than non C-allele carriers. Adiponectin levels were lower in C-allele carriers (delta total group: -11.6 ± 1.0 mg/dL: p = 0.02) too. In C-allele carriers, logistic regression analysis showed an increased risk of hypertriglyceridemia (odds ratio [OR] = 2.1, 95% confidence interval [CI] = 1.2-3.4, p = 0.001) and percentage of low-HDL-C (OR = 2.2, 95% CI = 1.3-3.7, p = 0.002) after adjusting by body mass index and age. CONCLUSIONS: C-allele carriers of rs662799 of APOA5 gene showed high rates of low levels of HDL and hypertriglyceridemia, with differences in triglyceride, HDL cholesterol, and adiponectin levels in Caucasian obese subjects.


Assuntos
Adipocinas , Síndrome Metabólica , Adulto , Apolipoproteína A-V/genética , Genótipo , Humanos , Obesidade , Polimorfismo de Nucleotídeo Único , Triglicerídeos
13.
EBioMedicine ; 70: 103521, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34388518

RESUMO

BACKGROUND: Liver fibrosis risk is a heritable trait, the outcome of which is the net deposition of extracellular matrix by hepatic stellate cell-derived myofibroblasts. Whereas nucleotide sequence variations have been extensively studied in liver fibrosis, the role of copy number variations (CNV) in which genes exist in abnormal numbers of copies (mostly due to duplication or deletion) has had limited exploration. METHODS: The impact of the XPO4 CNV on histological liver damage was examined in a cohort comprised 646 Caucasian patients with biopsy-proven MAFLD and 170 healthy controls. XPO4 expression was modulated and function was examined in human and animal models. FINDINGS: Here we demonstrate in a cohort of 816 subjects, 646 with biopsy-proven metabolic associated liver disease (MAFLD) and 170 controls, that duplication in the exportin 4 (XPO4) CNV is associated with the severity of liver fibrosis. Functionally, this occurs via reduced expression of hepatic XPO4 that maintains sustained activation of SMAD3/SMAD4 and promotes TGF-ß1-mediated HSC activation and fibrosis. This effect was mediated through termination of nuclear SMAD3 signalling. XPO4 demonstrated preferential binding to SMAD3 compared to other SMADs and led to reduced SMAD3-mediated responses as shown by attenuation of TGFß1 induced SMAD transcriptional activity, reductions in the recruitment of SMAD3 to target gene promoters following TGF-ß1, as well as attenuation of SMAD3 phosphorylation and disturbed SMAD3/SMAD4 complex formation. INTERPRETATION: We conclude that a CNV in XPO4 is a critical mediator of fibrosis severity and can be exploited as a therapeutic target for liver fibrosis. FUNDING: ME and JG are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; a National Health and Medical Research Council of Australia (NHMRC) Program Grant (APP1053206) and Project and ideas grants (APP2001692, APP1107178 and APP1108422). AB is supported by an Australian Government Research Training Program (RTP) scholarship. EB is supported by Horizon 2020 under grant 634413 for the project EPoS.


Assuntos
Variações do Número de Cópias de DNA , Fígado Gorduroso/genética , Carioferinas/genética , Cirrose Hepática/genética , Adulto , Animais , Linhagem Celular , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Feminino , Humanos , Carioferinas/metabolismo , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Proteína Smad3/metabolismo , Proteína Smad4/metabolismo , Fator de Crescimento Transformador beta/metabolismo
14.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200950

RESUMO

Sepsis is a major health problem worldwide. It is a time-dependent disease, with a high rate of morbidity and mortality. In this sense, an early diagnosis is essential to reduce these rates. The progressive increase of both the incidence and prevalence of sepsis has translated into a significant socioeconomic burden for health systems. Currently, it is the leading cause of noncoronary mortality worldwide and represents one of the most prevalent pathologies both in hospital emergency services and in intensive care units. In this article, we review the role of both endothelial dysfunction and neutrophil dysregulation in the physiopathology of this disease. The lack of a key symptom in sepsis makes it difficult to obtain a quick and accurate diagnosis of this condition. Thus, it is essential to have fast and reliable diagnostic tools. In this sense, the use of biomarkers can be a very important alternative when it comes to achieving these goals. Both new biomarkers and treatments related to endothelial dysfunction and neutrophil dysregulation deserve to be further investigated in order to open new venues for the diagnosis, treatment and prognosis of sepsis.


Assuntos
Endotélio Vascular/patologia , Neutrófilos/patologia , Sepse/fisiopatologia , Animais , Humanos , Sepse/etiologia
15.
Adv Sci (Weinh) ; 8(11): 2004168, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34141520

RESUMO

Fibroblast growth factor 21 (FGF21) is a liver-derived hormone with pleiotropic beneficial effects on metabolism. Paradoxically, FGF21 levels are elevated in metabolic diseases. Interventions that restore metabolic homeostasis reduce FGF21. Whether abnormalities in FGF21 secretion or resistance in peripheral tissues is the initiating factor in altering FGF21 levels and function in humans is unknown. A genetic approach is used to help resolve this paradox. The authors demonstrate that the primary event in dysmetabolic phenotypes is the elevation of FGF21 secretion. The latter is regulated by translational reprogramming in a genotype- and context-dependent manner. To relate the findings to tissues outcomes, the minor (A) allele of rs838133 is shown to be associated with increased hepatic inflammation in patients with metabolic associated fatty liver disease. The results here highlight a dominant role for translation of the FGF21 protein to explain variations in blood levels that is at least partially inherited. These results provide a framework for translational reprogramming of FGF21 to treat metabolic diseases.


Assuntos
Fígado Gorduroso/sangue , Fígado Gorduroso/complicações , Fatores de Crescimento de Fibroblastos/sangue , Inflamação/sangue , Inflamação/complicações , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Fígado Gorduroso/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Inflamação/metabolismo , Fígado/metabolismo
16.
J Hepatol ; 75(4): 786-794, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34090928

RESUMO

BACKGROUND & AIMS: Non-invasive scoring systems (NSS) are used to identify patients with non-alcoholic fatty liver disease (NAFLD) who are at risk of advanced fibrosis, but their reliability in predicting long-term outcomes for hepatic/extrahepatic complications or death and their concordance in cross-sectional and longitudinal risk stratification remain uncertain. METHODS: The most common NSS (NFS, FIB-4, BARD, APRI) and the Hepamet fibrosis score (HFS) were assessed in 1,173 European patients with NAFLD from tertiary centres. Performance for fibrosis risk stratification and for the prediction of long-term hepatic/extrahepatic events, hepatocarcinoma (HCC) and overall mortality were evaluated in terms of AUC and Harrell's c-index. For longitudinal data, NSS-based Cox proportional hazard models were trained on the whole cohort with repeated 5-fold cross-validation, sampling for testing from the 607 patients with all NSS available. RESULTS: Cross-sectional analysis revealed HFS as the best performer for the identification of significant (F0-1 vs. F2-4, AUC = 0.758) and advanced (F0-2 vs. F3-4, AUC = 0.805) fibrosis, while NFS and FIB-4 showed the best performance for detecting histological cirrhosis (range AUCs 0.85-0.88). Considering longitudinal data (follow-up between 62 and 110 months), NFS and FIB-4 were the best at predicting liver-related events (c-indices>0.7), NFS for HCC (c-index = 0.9 on average), and FIB-4 and HFS for overall mortality (c-indices >0.8). All NSS showed limited performance (c-indices <0.7) for extrahepatic events. CONCLUSIONS: Overall, NFS, HFS and FIB-4 outperformed APRI and BARD for both cross-sectional identification of fibrosis and prediction of long-term outcomes, confirming that they are useful tools for the clinical management of patients with NAFLD at increased risk of fibrosis and liver-related complications or death. LAY SUMMARY: Non-invasive scoring systems are increasingly being used in patients with non-alcoholic fatty liver disease to identify those at risk of advanced fibrosis and hence clinical complications. Herein, we compared various non-invasive scoring systems and identified those that were best at identifying risk, as well as those that were best for the prediction of long-term outcomes, such as liver-related events, liver cancer and death.


Assuntos
Hepatopatia Gordurosa não Alcoólica/complicações , Valor Preditivo dos Testes , Projetos de Pesquisa/normas , Tempo , Adulto , Área Sob a Curva , Estudos Transversais , Feminino , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/mortalidade , Prognóstico , Curva ROC , Reprodutibilidade dos Testes , Projetos de Pesquisa/tendências , Índice de Gravidade de Doença
17.
Liver Int ; 41(9): 2076-2086, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33896100

RESUMO

BACKGROUND AND AIM: Histological score systems may not fully capture the essential nonalcoholic steatohepatitis (NASH) features, which is one of the leading causes of screening failure in clinical trials. We assessed the NASH distribution and its components across the fibrosis stages and their impact on the prognosis and their relationship with the concept of metabolic-associated fatty liver disease (MAFLD). METHODS: Spanish multicenter study including 1893 biopsy-proven nonalcoholic fatty liver disease (NAFLD) patients from HEPAmet registry. NASH was diagnosed by NAS score ≥4 (including steatosis, ballooning and lobular inflammation) and fibrosis by Kleiner score. The presence of MAFLD was determined. Progression to cirrhosis, first episode of decompensated cirrhosis and death were collected during the follow-up (4.7 ± 3.8 years). RESULTS: Fibrosis was F0 34.3% (649/1893), F1 27% (511/1893), F2 16.5% (312/1893), F3 15% (284/1893) and F4 7.2% (137/1893). NASH diagnosis 51.9% (982/1893), and its individual components (severe steatosis, ballooning and lobular inflammation), increased from F0 (33.6%) to F2 (68.6%), and decreased significantly in F4 patients (51.8%) (P = .0001). More than 70% of non-NASH patients showed some inflammatory activity (ballooning or lobular inflammation), showing a similar MAFLD rate than NASH (96.2% [945/982] vs. 95.2% [535/562]) and significantly higher than nonalcoholic fatty liver (NAFL) subjects (89.1% [311/349]) (P < .0001). Progression to cirrhosis was similar between NASH (9.5% [51/539]) and indeterminate NASH (7.9% [25/316]), and higher than steatosis (5% [14/263]) (logRank 8.417; P = .015). Death and decompensated cirrhosis were similar between these. CONCLUSIONS: The prevalence of steatohepatitis decreased in advanced liver disease. However, most of these patients showed some inflammatory activity histologically and had metabolic disturbances. These findings should be considered in clinical trials whose main aim is to prevent cirrhosis progression and complications, liver transplant and death.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Biópsia , Humanos , Fígado/patologia , Cirrose Hepática/patologia , Estudos Longitudinais , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/patologia
18.
Rev Esp Enferm Dig ; 113(6): 396-403, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33222473

RESUMO

OBJECTIVES: to establish the clinical and economic consequences (resource utilization and healthcare costs) of non-alcoholic fatty liver in the setting of the usual clinical practice in Spain. PATIENTS AND METHODS: an observational, retrospective study was performed based on a review of the medical records of adult patients ≥ 18 years of age who sought medical care from 2017 to 2018. Patients were categorized into two groups according to fibrosis stage (estimation method: FIB-4): a) F0-F2; and b) F3-F4 (advanced fibrosis). Follow-up lasted one year. Primary endpoints included comorbidity, concomitant medication, resource utilization and costs. Results were analyzed using a multivariate approach with p < 0.05. RESULTS: a total of 8,151 patients were recruited with a mean age of 61.1 years and 51.5 % were male. By group: a) mild fibrosis n = 7,127, 87.4 %; and b) advanced fibrosis n = 1,024, 12.6 % (6.8 % with liver cirrhosis). The most common comorbidities included 63 % dyslipidemia, 52 % obesity, 52 % hypertension and 35 % diabetes. The average number of drugs used was 2.1 per patient. Patients with advanced fibrosis (F3-F4) had a higher average number of concomitant medications (2.5 vs 2.1; p < 0.001) and a higher AST/ALT ratio (1.1 vs 0.8; p < 0.001). The average cost (patient-year) for subjects with advanced fibrosis, corrected for covariates, was higher (€1,812 vs €1,128, p < 0.001). Age, morbidity, concomitant medication, fibrosis stage and total costs were higher in patients with diabetes. CONCLUSIONS: patients with advanced fibrosis were associated with more comorbidity and concomitant medications, which resulted in higher healthcare costs for the National Health System.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Adulto , Biópsia , Custos de Cuidados de Saúde , Humanos , Fígado , Cirrose Hepática/epidemiologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Espanha/epidemiologia
19.
PLoS One ; 15(12): e0243590, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33306709

RESUMO

Metabolic associated fatty liver disease (MAFLD) is the most prevalent liver disease in Western nations, with high heritability. A recent study of Japanese patients with the disease suggested that TLL1 rs17047200 is associated with fibrosis; whether a similar association is observed in Caucasian patients with MAFLD is unknown. We investigated the association of the TLL1 rs17047200 polymorphism with liver fibrosis in a cohort of Caucasian patients with MAFLD (n = 728). We also investigated whether TLL1 expression is altered during liver injury in humans, in murine models of fibrosis, and in in-vitro. While TLL1 expression is upregulated in the liver of humans with MAFLD and in mice, the rs17047200 variant was not associated with fibrosis or any other histological features, or with hepatic TLL1 expression. In conclusion, the TLL1 rs17047200 variant is not a risk variant for fibrosis in Caucasian patients with MAFLD. However, TLL1 could be involved in the pathogenesis of liver fibrosis.


Assuntos
Fígado Gorduroso/genética , Cirrose Hepática/genética , Polimorfismo de Nucleotídeo Único , Metaloproteases Semelhantes a Toloide/genética , Adulto , Animais , Estudos de Coortes , Fígado Gorduroso/complicações , Feminino , Variação Genética , Humanos , Cirrose Hepática/complicações , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Regulação para Cima
20.
Contemp Clin Trials ; 98: 106175, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33045403

RESUMO

Non-Alcoholic Fatty Liver Disease (NAFLD), a progressive liver disease that is closely associated with obesity, type 2 diabetes, hypertension and dyslipidaemia, represents an increasing global public health challenge. There is significant variability in the disease course: the majority exhibit only fat accumulation in the liver but a significant minority develop a necroinflammatory form of the disease (non-alcoholic steatohepatitis, NASH) that may progress to cirrhosis and hepatocellular carcinoma. At present our understanding of pathogenesis, disease natural history and long-term outcomes remain incomplete. There is a need for large, well characterised patient cohorts that may be used to address these knowledge gaps and to support the development of better biomarkers and novel therapies. The European NAFLD Registry is an international, prospectively recruited observational cohort study that aims to establish a large, highly-phenotyped patient cohort and linked bioresource. Here we describe the infrastructure, data management and monitoring plans, and the standard operating procedures implemented to ensure the timely and systematic collection of high-quality data and samples. Already recruiting subjects at secondary/tertiary care centres across Europe, the Registry is supporting the European Union IMI2-funded LITMUS 'Liver Investigation: Testing Marker Utility in Steatohepatitis' consortium, which is a major international effort to robustly validate biomarkers that diagnose, risk stratify and/or monitor NAFLD progression and liver fibrosis stage. The European NAFLD Registry has the demonstrable capacity to support research and biomarker development at scale and pace.


Assuntos
Diabetes Mellitus Tipo 2 , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Estudos de Coortes , Humanos , Fígado/patologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/epidemiologia , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Estudos Longitudinais , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/terapia , Sistema de Registros
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