Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
1.
J Hepatol ; 77(3): 596-606, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35405176

RESUMO

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disorders and has a strong heritable component. The aim of this study was to identify new loci that contribute to severe NAFLD by examining rare variants. METHODS: We performed whole-exome sequencing in individuals with NAFLD and advanced fibrosis or hepatocellular carcinoma (n = 301) and examined the enrichment of likely pathogenic rare variants vs. the general population. This was followed by validation at the gene level. RESULTS: In patients with severe NAFLD, we observed an enrichment of the p.P426L variant (rs143545741 C>T; odds ratio [OR] 5.26, 95% CI 2.1-12.6; p = 0.003) of autophagy-related 7 (ATG7), which we characterized as a loss-of-function, vs. the general population, and an enrichment in rare variants affecting the catalytic domain (OR 13.9; 95% CI 1.9-612; p = 0.002). In the UK Biobank cohort, loss-of-function ATG7 variants increased the risk of cirrhosis and hepatocellular carcinoma (OR 3.30; 95% CI 1.1-7.5 and OR 12.30, 95% CI 2.6-36, respectively; p <0.001 for both). The low-frequency loss-of-function p.V471A variant (rs36117895 T>C) was also associated with severe NAFLD in the clinical cohort (OR 1.7; 95% CI 1.2-2.5; p = 0.003), predisposed to hepatocellular ballooning (p = 0.007) evolving to fibrosis in the Liver biopsy cohort (n = 2,268), and was associated with liver injury in the UK Biobank (aspartate aminotransferase levels, p <0.001), with a larger effect in severely obese individuals in whom it was linked to hepatocellular carcinoma (p = 0.009). ATG7 protein localized to periportal hepatocytes, particularly in the presence of ballooning. In the Liver Transcriptomic cohort (n = 125), ATG7 expression correlated with suppression of the TNFα pathway, which was conversely upregulated in p.V471A carriers. CONCLUSIONS: We identified rare and low-frequency ATG7 loss-of-function variants that promote NAFLD progression by impairing autophagy and facilitating ballooning and inflammation. LAY SUMMARY: We found that rare mutations in a gene called autophagy-related 7 (ATG7) increase the risk of developing severe liver disease in individuals with dysmetabolism. These mutations cause an alteration in protein function and impairment of self-renewal of cellular content, leading to liver damage and inflammation.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Proteína 7 Relacionada à Autofagia/genética , Biópsia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Humanos , Inflamação/patologia , Fígado/patologia , Cirrose Hepática/complicações , Neoplasias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/complicações
2.
Am J Hematol ; 95(2): 167-177, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31724192

RESUMO

Iron overload heritability remains partly unexplained. By performing whole exome sequencing in three patients with a clinical phenotype of hemochromatosis not accounted by known genetic risk factors, we identified in all patients rare variants predicted to alter activity of Neuromedin-B receptor (NMBR). Coding NMBR mutations were enriched in 129 patients with hereditary hemochromatosis or iron overload phenotype, as compared to ethnically matched controls, including 100 local healthy blood donors and 1000Genomes project participants (15.5% vs 5%, P = .0038 at burden test), and were associated with higher transferrin saturation in regular blood donors (P = .04). Consistently, in 191 patients with nonalcoholic fatty liver, the most common low-frequency p.L390 M variant was independently associated with higher ferritin (P = .03). In 58 individuals, who underwent oral iron challenge, carriage of the p.L390 M variant was associated with higher transferrin saturation and lower hepcidin release. Furthermore, the circulating concentration of the natural NMBR ligand, Neuromedin-B, was reduced in response to iron challenge. It was also decreased in individuals carrying the p.L390 M variant and with hemochromatosis in parallel with increased transferrin saturation. In mice, Nmbr was induced by chronic dietary iron overload in the liver, gut, pancreas, spleen, and skeletal muscle, while Nmb was downregulated in gut, pancreas and spleen. Finally, Nmb amplified holo-transferrin dependent induction of hepcidin in primary mouse hepatocytes, which was associated with Jak2 induction and abolished by the NMBR antagonist PD168368. In conclusion, NMBR natural variants were enriched in patients with iron overload, and associated with facilitated iron absorption, possibly related to a defect of iron-induced hepcidin release.


Assuntos
Sobrecarga de Ferro , Ferro/sangue , Mutação de Sentido Incorreto , Hepatopatia Gordurosa não Alcoólica , Receptores da Bombesina , Adulto , Idoso , Substituição de Aminoácidos , Animais , Feminino , Ferritinas/sangue , Ferritinas/genética , Humanos , Sobrecarga de Ferro/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/genética , Receptores da Bombesina/genética , Receptores da Bombesina/metabolismo , Transferrina/genética , Transferrina/metabolismo
3.
Sci Transl Med ; 14(637): eabh3831, 2022 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-35320000

RESUMO

Inflammation has profound but poorly understood effects on metabolism, especially in the context of obesity and nonalcoholic fatty liver disease (NAFLD). Here, we report that hepatic interferon regulatory factor 3 (IRF3) is a direct transcriptional regulator of glucose homeostasis through induction of Ppp2r1b, a component of serine/threonine phosphatase PP2A, and subsequent suppression of glucose production. Global ablation of IRF3 in mice on a high-fat diet protected against both steatosis and dysglycemia, whereas hepatocyte-specific loss of IRF3 affects only dysglycemia. Integration of the IRF3-dependent transcriptome and cistrome in mouse hepatocytes identifies Ppp2r1b as a direct IRF3 target responsible for mediating its metabolic actions on glucose homeostasis. IRF3-mediated induction of Ppp2r1b amplified PP2A activity, with subsequent dephosphorylation of AMPKα and AKT. Furthermore, suppression of hepatic Irf3 expression with antisense oligonucleotides reversed obesity-induced insulin resistance and restored glucose homeostasis in obese mice. Obese humans with NAFLD displayed enhanced activation of liver IRF3, with reversion after bariatric surgery. Hepatic PPP2R1B expression correlated with HgbA1C and was elevated in obese humans with impaired fasting glucose. We therefore identify the hepatic IRF3-PPP2R1B axis as a causal link between obesity-induced inflammation and dysglycemia and suggest an approach for limiting the metabolic dysfunction accompanying obesity-associated NAFLD.


Assuntos
Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Animais , Resistência à Insulina/fisiologia , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/metabolismo , Camundongos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/genética , Obesidade/complicações , Obesidade/metabolismo
4.
Mol Metab ; 53: 101275, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34153521

RESUMO

OBJECTIVE: Neddylation is a druggable and reversible ubiquitin-like post-translational modification upregulated in many diseases, including liver fibrosis, hepatocellular carcinoma, and more recently, non-alcoholic fatty liver disease (NAFLD). Herein, we propose to address the effects of neddylation inhibition and the underlying mechanisms in pre-clinical models of NAFLD. METHODS: Hepatic neddylation measured by immunohistochemical analysis and NEDD8 serum levels measured by ELISA assay were evaluated in NAFLD clinical and pre-clinical samples. The effects of neddylation inhibition by using a pharmacological small inhibitor, MLN4924, or molecular approaches were assessed in isolated mouse hepatocytes and pre-clinical mouse models of diet-induced NAFLD, male adult C57BL/6 mice, and the AlfpCre transgenic mice infected with AAV-DIO-shNedd8. RESULTS: Neddylation inhibition reduced lipid accumulation in oleic acid-stimulated mouse primary hepatocytes and ameliorated liver steatosis, preventing lipid peroxidation and inflammation in the mouse models of diet-induced NAFLD. Under these conditions, increased Deptor levels and the concomitant repression of mTOR signaling were associated with augmented fatty acid oxidation and reduced lipid content. Moreover, Deptor silencing in isolated mouse hepatocytes abolished the anti-steatotic effects mediated by neddylation inhibition. Finally, serum NEDD8 levels correlated with hepatic neddylation during the disease progression in the clinical and pre-clinical models CONCLUSIONS: Overall, the upregulation of Deptor, driven by neddylation inhibition, is proposed as a novel effective target and therapeutic approach to tackle NAFLD.


Assuntos
Ácidos Graxos/metabolismo , Hepatócitos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Adolescente , Adulto , Idoso , Animais , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Transdução de Sinais , Adulto Jovem
5.
Curr Pharm Des ; 24(38): 4566-4573, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30659533

RESUMO

Nonalcoholic fatty liver disease (NAFLD), now the leading cause of liver damage worldwide, is epidemiologically associated with obesity, insulin resistance and type 2 diabetes, and is a potentially progressive condition to advanced liver fibrosis and hepatocellular carcinoma. However, there is huge interindividual variability in liver disease susceptibility. Inherited factors also play an important role in determining disease predisposition. During the last years, common variants in PNPLA3, TM6SF2, MBOAT7 and GCKR have been demonstrated to predispose to the full spectrum of NAFLD pathology by facilitating hepatic fat accumulation in the presence of environmental triggers. Other variants regulating inflammation and fibrogenesis then modulate liver disease progression in those at higher risk. Evidence is also accumulating that rare variants are involved in disease predisposition. In the future, evaluation of genetic risk factors may be exploited to stratify the risk of liver-related complications of the disease, and to guide hepatocellular carcinoma surveillance and choose pharmacological therapy.


Assuntos
Resistência à Insulina/genética , Hepatopatia Gordurosa não Alcoólica/genética , Apolipoproteínas B/genética , Progressão da Doença , Interação Gene-Ambiente , Humanos , Lipase/genética , Fígado/metabolismo , Proteínas de Membrana/genética , Mutação , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Polimorfismo Genético
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa