Dysregulation of the Splicing Machinery Is Associated to the Development of Nonalcoholic Fatty Liver Disease
| Autor: | Manuel de la Mata, Rhonda D. Kineman, Manuel Rodríguez-Perálvarez, Marina E. Sánchez-Frías, Raúl M. Luque, Gustavo Ferrín, Rafael Sánchez-Sánchez, Sandra González-Rubio, Sebastián Ventura, Manuel D. Gahete, Mercedes del Rio-Moreno, Justo P. Castaño, Oscar Reyes, Jose Lopez-Miranda, Emilia Alors-Perez |
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| Rok vydání: | 2019 |
| Předmět: |
Adult
Male 0301 basic medicine medicine.medical_specialty Spliceosome Cirrhosis Biopsy RNA Splicing Endocrinology Diabetes and Metabolism Clinical Biochemistry Cell Culture Techniques Bariatric Surgery Nerve Tissue Proteins Context (language use) Bioinformatics Biochemistry Heterogeneous-Nuclear Ribonucleoproteins 03 medical and health sciences 0302 clinical medicine Endocrinology Non-alcoholic Fatty Liver Disease Internal medicine Nonalcoholic fatty liver disease medicine Humans Obesity Postoperative Period Clinical Research Articles business.industry Biochemistry (medical) RNA-Binding Proteins Hep G2 Cells PTBP1 Middle Aged Endonucleases medicine.disease 030104 developmental biology Liver Lipogenesis RNA splicing Female 030211 gastroenterology & hepatology Steatosis business Polypyrimidine Tract-Binding Protein |
| Zdroj: | The Journal of Clinical Endocrinology & Metabolism. 104:3389-3402 |
| ISSN: | 1945-7197 0021-972X |
| Popis: | Context Nonalcoholic fatty liver disease (NAFLD) is a common obesity-associated pathology characterized by hepatic fat accumulation, which can progress to fibrosis, cirrhosis, and hepatocellular carcinoma. Obesity is associated with profound changes in gene-expression patterns of the liver, which could contribute to the onset of comorbidities. Objective As these alterations might be linked to a dysregulation of the splicing process, we aimed to determine whether the dysregulation in the expression of splicing machinery components could be associated with NAFLD. Participants We collected 41 liver biopsies from nonalcoholic individuals with obesity, with or without hepatic steatosis, who underwent bariatric surgery. Interventions The expression pattern of splicing machinery components was determined using a microfluidic quantitative PCR-based array. An in vitro approximation to determine lipid accumulation using HepG2 cells was also implemented. Results The liver of patients with obesity and steatosis exhibited a severe dysregulation of certain splicing machinery components compared with patients with obesity without steatosis. Nonsupervised clustering analysis allowed the identification of three molecular phenotypes of NAFLD with a unique fingerprint of alterations in splicing machinery components, which also presented distinctive hepatic and clinical-metabolic alterations and a differential response to bariatric surgery after 1 year. In addition, in vitro silencing of certain splicing machinery components (i.e., PTBP1, RBM45, SND1) reduced fat accumulation and modulated the expression of key de novo lipogenesis enzymes, whereas conversely, fat accumulation did not alter spliceosome components expression. Conclusion There is a close relationship between splicing machinery dysregulation and NAFLD development, which should be further investigated to identify alternative therapeutic targets. |
| Databáze: | OpenAIRE |
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