RT Journal Article
T1 Dysregulation of the Splicing Machinery Is Associated to the Development of Nonalcoholic Fatty Liver Disease.
A1 Del Rio-Moreno, Mercedes
A1 Alors-Perez, Emilia
A1 Gonzalez-Rubio, Sandra
A1 Ferrin, Gustavo
A1 Reyes, Oscar
A1 Rodriguez-Peralvarez, Manuel
A1 Sanchez-Frias, Marina E
A1 Sanchez-Sanchez, Rafael
A1 Ventura, Sebastian
A1 Lopez-Miranda, Jose
A1 Kineman, Rhonda D
A1 de la Mata, Manuel
A1 Castaño, Justo P
A1 Gahete, Manuel D
A1 Luque, Raul M
K1 Non-alcoholic Fatty Liver Disease
K1 Obesity
K1 Polypyrimidine Tract-Binding Protein
K1 Postoperative Period
K1 RNA Splicing
K1 RNA-Binding Proteins
AB 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.
PB Oxford University Press
YR 2019
FD 2019
LK http://hdl.handle.net/10668/13749
UL http://hdl.handle.net/10668/13749
LA en
NO 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
NO This work was funded by Instituto de Salud Carlos III and co-funded by European Union (ERDF/ESF, “Investing in your future,” PI17/002287, PI16/00264, PIE14/00005, CP15/00156); MINECO (BFU2016-80360-R,TIN2017-83445-P); Junta de Andaluc´ıa (BIO-0139, CTS1406, PI-0541-2013); and CIBERehd and CIBERobn. (CIBER is an initiative of Instituto de Salud Carlos III,Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain.) Financialsupport was also provided by Development Merit Award (BX001114) and U.S. National Institutes of Health (Grant R01DK088133 to R.D.K.).
DS RISalud
RD Apr 4, 2025