Obesity, metabolism & miscellaneous endocrinology
Natalia Hermán-Sánchez 1,2,3,4 , Juan L. López-Cánovas 1,2,3,4 , Antonio García-Estrada 1,2,3,4 , Mercedes del Rio-Moreno 1,2,3,4 , Prudencio Sáez-Martínez 1,2,3,4 , Marina E. Sánchez-Frias 1,3 , Víctor Amado 1,5,6 , Manuel de la Mata 1,5,6 , José Córdoba-Chacón 7 , André Sarmento-Cabral 1,2,3,4 , Manuel Rodríguez-Perálvarez 1,5,6 , Raúl M. Luque 1,2,3,4 & Manuel D. Gahete 1,2,3,4
1Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), 14004-Córdoba, Spain [email protected]; 2Department of Cell Biology, Physiology and Immunology, University of Córdoba, 14004-Córdoba, Spain; 3Reina Sofía University Hospital, 14004-Córdoba, Spain; 4CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), 14004-Córdoba, Spain; 5Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, 14004-Córdoba, Spain; 6CIBER Hepatic and Digestive Diseases (CIBERehd), 14004-Córdoba, Spain; 7Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois
Background: Hormonal signalling plays a key role in the progression of non-alcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC). However, the role of somatostatin (SST), cortistatin (CORT), neuronostatin (NST) and ghrelin systems in NAFLD-HCC progression has not been elucidated.
Objectives: To characterize the role of SST/CORT/NST and ghrelin systems in chronic liver disease and evaluate its clinical potential.
Methods: The expression of the SST/CORT/NST/ghrelin system components was analysed in retrospective cohorts [cohort 1 (n=93) and cohort 2 (n=58), HCC vs. adjacent; cirrhosis (n=39), and healthy livers (n=5)], in liver-derived cell lines (HepG2, Hep3b, SNU-387), in mouse models of NAFLD/non-alcoholic steatohepatitis (NASH)/cirrhosis and on in silico HCC cohorts (mRNA/protein). Proliferation after treatment with SST/CORT/NST and ghrelin (natural and synthetic peptides) was evaluated in cell lines and human liver primary cultures.
Results: Chronic liver disease is characterized by a progressive overexpression of SST and GPR107 (the NST receptor), the downregulation of SSTR1 and the stage-dependent alteration of CORT, SSTR2, GOAT-enzyme and GHSR1b from cirrhosis to HCC. Animal models of NAFLD/NASH exhibited SSTR3 and GRP107 overexpression and SSTR1, SSTR2 and ghrelin downregulation. GPR107 overexpression was validated in silico and correlated with aggressiveness (survival, tumor diameter, proliferation markers). In vitro assays revealed a receptor pattern-dependent decrease in proliferation of cell lines and primary cultures in response to SST, CORT, NST and SST analogues.
Conclusions: This study demonstrates an alteration of the SST/CORT/NST/ghrelin systems in human, animal, and cellular models of chronic liver disease, and suggest a potential prognostic/therapeutic role of some components, including SST-analogues and GPR107 in liver pathologies.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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