Publication:
Dysregulation of the Splicing Machinery Is Associated to the Development of Nonalcoholic Fatty Liver Disease.

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Date

2019

Authors

Del Rio-Moreno, Mercedes
Alors-Perez, Emilia
Gonzalez-Rubio, Sandra
Ferrin, Gustavo
Reyes, Oscar
Rodriguez-Peralvarez, Manuel
Sanchez-Frias, Marina E
Sanchez-Sanchez, Rafael
Ventura, Sebastian
Lopez-Miranda, Jose

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Oxford University Press
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Abstract

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. 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. We collected 41 liver biopsies from nonalcoholic individuals with obesity, with or without hepatic steatosis, who underwent bariatric surgery. 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. 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. There is a close relationship between splicing machinery dysregulation and NAFLD development, which should be further investigated to identify alternative therapeutic targets.

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MeSH Terms

Adult
Bariatric Surgery
Biopsy
Cell Culture Techniques
Endonucleases
Female
Hep G2 Cells
Heterogeneous-Nuclear Ribonucleoproteins
Humans
Liver
Male
Middle Aged
Nerve Tissue Proteins

DeCS Terms

Biopsia
Cirugía bariátrica
Endonucleasas
Hígado
Proteínas del tejido nervioso
Ribonucleoproteínas nucleares heterogéneas
Técnicas de cultivo de célula

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Keywords

Non-alcoholic Fatty Liver Disease, Obesity, Polypyrimidine Tract-Binding Protein, Postoperative Period, RNA Splicing, RNA-Binding Proteins

Citation

Del Río-Moreno M, Alors-Pérez E, González-Rubio S, Ferrín G, Reyes O, Rodríguez-Perálvarez M, et al. Dysregulation of the Splicing Machinery Is Associated to the Development of Nonalcoholic Fatty Liver Disease. J Clin Endocrinol Metab. 2019 Aug 1;104(8):3389-3402