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1.
J Lipid Res ; 60(1): 176-185, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30323112

RESUMO

Hydroxysteroid 17-ß dehydrogenase 13 (HSD17B13) is a lipid droplet-associated protein; its gene-encoding variants affect the chronic liver diseases, including nonalcoholic fatty liver disease (NAFLD). To estimate the effect of rs72613567, a splice variant with an adenine insertion (A-INS), on NAFLD susceptibility and severity, we performed a case-control study with 609 individuals. We investigated the effect of carrying the A-INS allele in 356 patients with biopsy-proven disease and explored the relationship between rs72613567 genotypes and the hepatic transcriptome. The A-INS allele protected against NAFLD [odds ratio (OR) per adenine allele = 0.667; 95% CI, 0.486-0.916; P = 0.012]; this effect was nonsignificant when logistic regression analysis included BMI. The A-INS allele protected against nonalcoholic steatohepatitis (NASH) (OR = 0.612; 95% CI, 0.388-0.964; P = 0.033), ballooning degeneration (OR = 0.474; 95% CI, 0.267-0.842; P = 0.01), lobular inflammation (OR = 0.475; 95% CI, 0.275-0.821; P = 0.007), and fibrosis (OR = 0.590; 95% CI, 0.361-0.965; P = 0.035). In patients carrying A-INS, HSD17B13 levels decreased proportionally to allele dosage. Whole-transcriptome genotype profiling showed overrepresented immune response-related pathways. Thus, the rs72613567 A-INS allele reduces the risk of NASH and progressive liver damage and may become a therapeutic target.


Assuntos
17-Hidroxiesteroide Desidrogenases/genética , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Polimorfismo de Nucleotídeo Único , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Perfilação da Expressão Gênica , Genótipo , Humanos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/imunologia
2.
Hepatology ; 61(2): 515-25, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25302781

RESUMO

UNLABELLED: We explored the role of transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 C/T nonsynonymous (p.Glu167Lys) variant in genetic susceptibility to nonalcoholic fatty liver disease (NAFLD) and disease severity. A total of 361 individuals (135 control subjects and 226 patients with histologically proven NAFLD) were included in a sample with 97% power for the additive genetic model. A discrete trait analysis of NAFLD showed that rs58542926 was associated with a modest risk of fatty liver (P = 0.038; odds ratio [OR]: 1.37; 95% confidence interval [CI]: 1.02-1.84); nevertheless, conditioning on patatin-like phospholipase domain-containing 3 (PNPLA3)-rs738409 abolished this effect. We did not observe an interaction between rs738409 and rs58542926 variants on the risk of NAFLD. We observed a significant association of rs58542926 and disease severity (P = 0.027), but not lobular inflammation or fibrosis; rs58542926 was not associated with levels of liver enzymes. An allelic test showed that the T (Lys167) allele was significantly associated with disease progression (P = 0.021; OR, 1.66; 95% CI: 1.08-2.55). A significant association was found with the histological degree of liver steatosis (ß, 0.15; standard error: 0.06; P = 0.0299) that was independent of rs738409. Homozygous carriers of the C (Glu167) allele showed increased risk for cardiovascular disease. TM6SF2 protein expression was decreased markedly in liver of NAFLD patients, compared to controls. In addition, TM6SF2 immunoreactivity was reduced in subjects carrying at least one copy of the T allele, consistent with a difference in liver allele-specific transcript abundance. CONCLUSION: rs58542926 is a low-frequency variant with a modest effect on NAFLD, suggesting that carriers of the T allele are slightly more likely to accumulate fat in the liver and develop nonalcoholic steatohepatitis than those without. TM6SF2 appears to play a significant role in disease biology.


Assuntos
Fígado/patologia , Proteínas de Membrana/genética , Hepatopatia Gordurosa não Alcoólica/genética , Adulto , Idoso , Alelos , Doenças Cardiovasculares/genética , Estudos de Casos e Controles , Progressão da Doença , Feminino , Fibrose , Predisposição Genética para Doença , Variação Genética , Humanos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/patologia , Polimorfismo de Nucleotídeo Único
3.
Gut ; 64(5): 800-12, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-24973316

RESUMO

OBJECTIVES: We used a screening strategy of global serum microRNA (miRNA) profiling, followed by a second stage of independent replication and exploration of liver expression of selected miRNAs to study: (1) the circulating miRNA signature associated with non-alcoholic fatty liver disease (NAFLD) progression and predictive power, (2) the role of miRNAs in disease biology and (3) the association between circulating miRNAs and features of the metabolic syndrome. METHODS: The study used a case-control design and included patients with NAFLD proven through biopsy and healthy controls. RESULTS: Among 84 circulating miRNAs analysed, miR-122, miR-192, miR-19a and miR-19b, miR-125b, and miR-375 were upregulated >2-fold (p<0.05) either in simple steatosis (SS) or non-alcoholic steatohepatitis (NASH). The most dramatic and significant fold changes were observed in the serum levels of miR-122 (7.2-fold change in NASH vs controls and 3.1-fold change in NASH vs SS) and miR-192 (4.4-fold change in NASH vs controls); these results were replicated in the validation set. The majority of serum miR-122 circulate in argonaute2-free forms. Circulating miR-19a/b and miR-125b were correlated with biomarkers of atherosclerosis. Liver miR-122 expression was 10-fold (p<0.03) downregulated in NASH compared with SS and was preferentially expressed at the edge of lipid-laden hepatocytes. In vitro exploration showed that overexpression of miR-122 enhances alanine aminotransferase activity. CONCLUSIONS: miR-122 plays a role of physiological significance in the biology of NAFLD; circulating miRNAs mirror the histological and molecular events occurring in the liver. NAFLD has a distinguishing circulating miRNA profile associated with a global dysmetabolic disease state and cardiovascular risk.


Assuntos
Fígado/patologia , MicroRNAs/sangue , Hepatopatia Gordurosa não Alcoólica/genética , RNA não Traduzido/sangue , Adulto , Antropometria/métodos , Proteínas Argonautas/sangue , Proteínas Argonautas/genética , Biomarcadores/sangue , Biópsia , Estudos de Casos e Controles , Células Cultivadas , Simulação por Computador , Feminino , Perfilação da Expressão Gênica/métodos , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Humanos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/patologia , Transaminases/metabolismo , Regulação para Cima/fisiologia
5.
Hepatol Commun ; 2(6): 654-665, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29881817

RESUMO

Long noncoding RNAs (lncRNAs) are functional molecules that orchestrate gene expression. To identify lncRNAs involved in nonalcoholic fatty liver disease (NAFLD) severity, we performed a multiscale study that included: (a) systems biology modeling that indicated metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) as a candidate lncRNA for exploring disease-related associations, (b) translational exploration in the clinical setting, and (c) mechanistic modeling. MALAT1 liver profiling was performed in three consecutive phases, including an exploratory stage (liver samples from patients with NAFLD who were morbidly obese [n = 47] and from 13 individuals with normal liver histology); a replication stage (patients with NAFLD and metabolic syndrome [n =49]); and a hypothesis-driven stage (patients with chronic hepatitis C and autoimmune liver diseases, [n = 65]). Liver abundance of MALAT1 was associated with NAFLD severity (P = 1 × 10-6); MALAT1 expression levels were up-regulated 1.75-fold (P = 0.029) and 3.6-fold (P = 0.012) in patients with nonalcoholic steatohepatitis compared to those diagnosed with simple steatosis (discovery and replication set, respectively; analysis of covariance adjusted by age, homeostasis model assessment, and body mass index). Quantification of liver vascular endothelial growth factor A messenger RNA, a target of MALAT1, revealed a significant correlation between the two RNAs (R, 0.58; P = 5 × 10-8). Increased levels of MALAT1 were also associated with autoimmune liver diseases. Interactome assessment uncovered significant biological pathways, including Janus kinase-signal transducers and activators of transcription and response to interferon-γ. Conclusion: Deregulated expression of MALAT1 stratifies patients into the histologic phenotypes associated with NAFLD severity. MALAT1 up-regulation seems to be a common molecular mechanism in immune-mediated chronic inflammatory liver damage. This suggests that convergent pathophenotypes (inflammation and fibrosis) share similar molecular mediators. (Hepatology Communications 2018;2:654-665).

6.
Hepatol Commun ; 2(9): 1030-1036, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30202818

RESUMO

We report on the presence of a rare nonsense mutation (rs149847328, p.Arg227Ter) in the glucokinase regulator (GCKR) gene in an adult patient with nonalcoholic fatty liver disease (NAFLD), morbid obesity, and type 2 diabetes; this patient developed a progressive histological form of the disease. Analysis of paired (5 years apart) liver biopsies (at baseline and follow-up) showed progression of simple steatosis to severe nonalcoholic steatohepatitis and cirrhosis. Study design involved an initial exploration that consisted of deep sequencing of 14 chromosomal regions in 96 individuals (64 of whom were patients with NAFLD who were diagnosed by liver biopsy that showed the full spectrum of histological severity). We further performed a replication study to explore the presence of rs149847328 that included a sample of 517 unrelated individuals in a case-control study (n = 390), including patients who were morbidly obese (n = 127). Exploration of sequence variation by next-generation sequencing of exons, exon-intron boundaries, and 5' and 3' untranslated regions of 14 genomic loci that encode metabolic enzymes of the tricarboxylic acid cycle revealed the presence of heterozygosity for the p.Arg227Ter mutation, the frequency of which is 0.0003963 (4:10,000; Exome Aggregation Consortium database). GCKR protein expression was markedly decreased in the liver of the affected patient compared with patients with NAFLD who carry the wild-type allele. Sequencing of the same 14 genomic loci in 95 individuals failed to reveal the rare mutation. The rarity of p.Arg227Ter was confirmed in a more extensive screening. Conclusion: While rare variants/mutations are difficult to detect in even reasonably large samples (frequency of the mutant allele of p.Arg227Ter was ~1:1,000 in our data set), the presence of this mutation should be suspected as potentially associated with NAFLD, particularly in young adults at the extreme of histological phenotypes. Hepatology Communications 2018;0:0-0).

7.
Sci Rep ; 6: 22528, 2016 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-26935030

RESUMO

Ballooning degeneration (BD) of hepatocytes is a distinguishing histological feature associated with the progression of nonalcoholic fatty liver disease (NAFLD). Under the assumption that NAFLD severity is associated with metabolic-stress we explored the hypothesis that heat shock 27 kDa protein 1 (HSP27), a protein chaperone involved in stress resistance and cytoskeletal-remodeling, might be deregulated in ballooned hepatocytes. We observed that fasting plasma glucose (fpG) (p = 0.00002), total cholesterol (p = 0.02) and triglycerides (p = 0.01) levels, and female sex (p = 0.01) were significantly associated with the presence of BD. A logistic regression model showed that BD was independently associated with fpG (p = 0.002); OR per unit of glucose concentration 1.05, 95% confidence interval 1.02-1.09. Furthermore, BD was associated with a significant 2.24-fold decrease in the expression level of HSP27-mRNA in comparison with absence of ballooning, p = 0.002. Ballooned hepatocytes showed very low HSP27 immunoreactivity compared with hepatocyes without ballooning (p = 0.009); HSP27 immunoreactivity was inversely correlated with fpG levels (R: -0.49, p = 0.01). In conclusion, BD is associated with down-regulation of liver HSP27 gene and protein expression, suggesting that ballooned hepatocytes fail to ensure a robust physiological response to metabolic-induced stress.


Assuntos
Regulação para Baixo , Proteínas de Choque Térmico HSP27/biossíntese , Hepatócitos/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Adulto , Feminino , Proteínas de Choque Térmico , Hepatócitos/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Chaperonas Moleculares , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/terapia
8.
Am J Clin Nutr ; 103(2): 422-34, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26791191

RESUMO

BACKGROUND: Extensive epidemiologic studies have shown that cardiovascular disease and the metabolic syndrome (MetS) are associated with serum concentrations of liver enzymes; however, fundamental characteristics of this relation are currently unknown. OBJECTIVE: We aimed to explore the role of liver aminotransferases in nonalcoholic fatty liver disease (NAFLD) and MetS. DESIGN: Liver gene- and protein-expression changes of aminotransferases, including their corresponding isoforms, were evaluated in a case-control study of patients with NAFLD (n = 42), which was proven through a biopsy (control subjects: n = 10). We also carried out a serum targeted metabolite profiling to the glycolysis, gluconeogenesis, and Krebs cycle (n = 48) and an exploration by the next-generation sequencing of aminotransferase genes (n = 96). An in vitro study to provide a biological explanation of changes in the transcriptional level and enzymatic activity of aminotransferases was included. RESULTS: Fatty liver was associated with a deregulated liver expression of aminotransferases, which was unrelated to the disease severity. Metabolite profiling showed that serum aminotransferase concentrations are a signature of liver metabolic perturbations, particularly at the amino acid metabolism and Krebs cycle level. A significant and positive association between systolic hypertension and liver expression levels of glutamic-oxaloacetic transaminase 2 (GOT2) messenger RNA (Spearman R = 0.42, P = 0.03) was observed. The rs6993 located in the 3' untranslated region of the GOT2 locus was significantly associated with features of the MetS, including arterial hypertension [P = 0.028; OR: 2.285 (95% CI: 1.024, 5.09); adjusted by NAFLD severity] and plasma lipid concentrations. CONCLUSIONS: In the context of an abnormal hepatic triglyceride accumulation, circulating aminotransferases rise as a consequence of the need for increased reactions of transamination to cope with the liver metabolic derangement that is associated with greater gluconeogenesis and insulin resistance. Hence, to maintain homeostasis, the liver upregulates these enzymes, leading to changes in the amounts of amino acids released into the circulation.


Assuntos
Alanina Transaminase/metabolismo , Aspartato Aminotransferase Citoplasmática/metabolismo , Aspartato Aminotransferase Mitocondrial/metabolismo , Indução Enzimática , Gluconeogênese , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Alanina Transaminase/sangue , Alanina Transaminase/genética , Aminoácidos/metabolismo , Aspartato Aminotransferase Citoplasmática/sangue , Aspartato Aminotransferase Citoplasmática/genética , Aspartato Aminotransferase Mitocondrial/sangue , Aspartato Aminotransferase Mitocondrial/genética , Biomarcadores/sangue , Estudos de Casos e Controles , Linhagem Celular Tumoral , Ciclo do Ácido Cítrico , Estudos de Coortes , Estudos Transversais , Fígado Gorduroso/etiologia , Feminino , Humanos , Resistência à Insulina , Isoenzimas/sangue , Isoenzimas/genética , Isoenzimas/metabolismo , Fígado/patologia , Fígado/fisiopatologia , Masculino , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Polimorfismo de Nucleotídeo Único
9.
Rev Esp Cardiol ; 55(5): 505-13, 2002 May.
Artigo em Espanhol | MEDLINE | ID: mdl-12015931

RESUMO

INTRODUCTION AND OBJECTIVES: Myxomas are the most common type of primary cardiac tumors. The aim of this study was to analyze the clinical forms of presentation of cardiac myxoma, the postoperative evolution, and the possibility of recurrence and tumoral embolism. PATIENTS AND METHOD: From July 1992 to March 1999, 31 patients with myxoma were studied. Cell cycles (ploidy pattern of the tumoral DNA) were studied in 12 patients to evaluate the risk of recurrence and tumoral embolism. RESULTS: The most frequent clinical manifestations were constitutional symptoms (74%), dyspnea (45%), and embolism (41%). Smaller-diameter myxomas correlated independently with tumoral embolism (45%). The in-hospital mortality was 3.2%, no deaths were observed during follow-up (mean: 4.8 years). No patients had clinical or echocardiographic signs of tumoral recurrence. Patients with tumoral embolism (n = 8) were compared with patients without embolism (n = 4). Patients who suffered embolism had higher S phase > 7 and/or DNA index > 1.2 (4/4 patients [100%], p= 0.061) than patients without embolism (2/8 patients [25%]). Cytometry of the only recurrent tumor (second operation) revealed a diploid tumor with a significantly more frequent S phase (10%) than in sporadic myxomas (4.27 2.32%, p = 0.039). CONCLUSIONS: Constitutional symptoms, dyspnea, and tumor embolism were the most frequent clinical manifestations. Clinical and anatomopathologic characteristics and the cell cycle were not significantly related to tumoral embolism, but there was a tendency toward a higher proportion of cells in S phase and a higher DNA index in tumors associated with embolism. The S phase was significantly more frequent in the only case of recurrent myxoma and could be a potential marker of recurrence.


Assuntos
Neoplasias Cardíacas/cirurgia , Mixoma/cirurgia , Adulto , Idoso , DNA de Neoplasias/química , Feminino , Neoplasias Cardíacas/diagnóstico , Neoplasias Cardíacas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Mixoma/diagnóstico , Mixoma/patologia , Células Neoplásicas Circulantes/patologia , Recidiva , Estudos Retrospectivos
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