Hepatic Steatosis Is Associated with Alterations in Splicing Machinery Components: Clinical and Pathophysiological Implications

Presentation Number: LB MON 66
Date of Presentation: April 3rd, 2017

Manuel D. Gahete*1, Mercedes del Rio-Moreno2, Emilia Alors-Perez3, Sergio Pedraza-Arevalo4, André Sarmento-Cabral5, Fernando L-Lopez6, Sandra Gonzalez-Rubio7, Gustavo Ferrin8, M Rodríguez-Perálvarez7, Rhonda D. Kineman9, Alejandro Ibañez-Costa1, Manuel de la Mata7, Justo P Castano10 and Raul M. Luque10
1University of Córdoba; Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/Hospital Universitario Reina Sofia, and CIBER de la Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain, 21Maimonides Institute of Biomedical Research of Cordoba (IMIBIC); Reina Sofia University Hospital (HURS); Department of Cell Biology, Physiology and Immunology, University of Cordoba (UCO), Cordoba, Spain, 31Maimonides Institute of Biomedical Research of Cordoba (IMIBIC); Reina Sofia University Hospital (HURS); Department of Cell Biology, Physiology and Immunology, University of Cordoba (UCO), 4Maimonides Institute of Biomedical Research of Cordoba (IMIBIC); Reina Sofia University Hospital (HURS); Department of Cell Biology, Physiology and Immunology, University of Cordoba (UCO), Cordoba, Spain, 5University of Cordoba; Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/Hospital Universitario Reina Sofia, CIBER de la Fisiopatología de la Obesidad y Nutrición (CIBERobn) and ceiA3, Córdoba, Spain, 6University of Cordoba, 7Department of Hepatology and Liver Transplantation, HURS/IMIBIC; CIBER Liver and Digestive Diseases (CIBERehd), Cordoba, Spain, 8Department of Hepatology and Liver Transplantation, HURS/IMIBIC; CIBER Liver and Digestive Diseases (CIBERehd),, Cordoba, Spain, 9& Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, IL, 10Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/Hospital Universitario Reina Sofia, CIBER de la Fisiopatología de la Obesidad y Nutrición (CIBERobn) and ceiA3, Córdoba, Spain

Abstract

Hepatic steatosis is a common obesity-associated pathology characterized by hepatic fat accumulation, which can progress to liver fibrosis, cirrhosis and hepatocellular carcinoma. Obesity is associated with profound changes in gene expression patterns, including aberrant expression of splicing variants that could contribute to associated-comorbidities. Since the appearance of alternative splicing variants might be linked to a dysregulation of the cellular machinery responsible for this process [(spliceosome components and splicing factors (SFs)], the objective of this study was to determine the association between the expression pattern of the components of this machinery and hepatic steatosis. Firstly, we determined the expression levels of selected components of the major (n=13) and minor (n=4) spliceosomes and SFs (n=28) using a qPCR-based array in liver biopsies from obese women (IMC>30) with (n=32) and without (n=9) hepatic steatosis. The results revealed that the liver of steatotic patients exhibit a profound dysregulation of certain spliceosome components and SFs compared to non-steatotic patients (e.g. RNU6, RBM22), although these alterations were not associated with the level of hepatic steatosis. However, non-supervised clustering analysis revealed the existence of groups of steatotic patients with similar alterations in spliceosome components and SFs, which presented different hepatic and clinical-metabolic alterations (e.g. ALT, hyperglycemia, hyperinsulinemia, etc.). Supporting this association, preclinical models revealed that splicing machinery components (e.g. RBM22) were also altered during high-fat feeding-induced experimental liver steatosis. Finally, in vitro approaches with liver cell lines demonstrated that fat accumulation altered the expression of certain spliceosome components and SFs and that the modulation (overexpression/silencing) of certain splicing machinery components altered fat accumulation, indicating a bidirectional crosstalk. Therefore, these results suggest a close relationship between the development of hepatic steatosis and its associated comorbidities with the dysregulation of splicing machinery, which may provide novel diagnostic/therapeutic tools for this pathology.

 

Nothing to Disclose: MDG, MD, EA, SP, AS, FL, SG, GF, MR, RDK, AI, MD, JPC, RML