Paola Dongiovanni1, Marica Meroni2, Salvatore Petta3, Miriam Longo4, Anna Alisi5, Giorgio Soardo6, Luca Valenti7, Luca Miele8, Stefania Grimaudo3, Grazia Pennisi3, Grieco Antonio8, Dario Consonni9, Silvia Fargion1, Anna Ludovica Fracanzani10. 1. General Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy. 2. General Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy; Departments of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy. 3. Sezione di Gastroenterologia e Epatologia, PROMISE, University of Palermo, Italy. 4. General Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy. 5. Research Unit of Molecular Genetics of Complex Phenotypes, "Bambino Gesù" Children's Hospital IRCCS, Rome, Italy. 6. Department of Medical Area (DAME), University of Udine and Italian Liver Foundation, Bldg Q AREA Science Park - Basovizza Campus, Trieste, Italy. 7. Translational Medicine, University of Milan, Fondazione IRCCS Cà Granda Pad Marangoni, Milan, Italy. 8. Area Medicina Interna, Gastroenterologia e Oncologia Medica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. 9. Epidemiology Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy. 10. General Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy; Departments of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy. Electronic address: anna.fracanzani@unimi.it.
Abstract
BACKGROUND & AIMS: Neurotensin (NTS), a 13-aminoacid peptide localized in central nervous system and gastrointestinal tract, is involved in lipid metabolism and promotes various cancers onset mainly by binding to neurotensin receptor 1 (NTSR1). Increased plasma levels of pro-NTS, the stable NTS precursor, have been associated with type 2 diabetes (T2D), cardiovascular diseases and metabolic associated fatty liver disease (MAFLD). We aimed to evaluate 1) the impact of NTS rs1800832 and NTSR1 rs6090453 genetic variants on liver damage in 1166 MAFLD European individuals, 2) the relation between NTS variant and circulating pro-NTS and 3) the hepatic NTS expression by RNAseq transcriptomic analysis in 125 bariatric patients. RESULTS: The NTS rs1800832 G allele was associated with hepatic fibrosis (OR 1.27, 95% confidence interval (CI). 1.02-1.58; p = 0.03), even more in carriers of both NTS and NTSR1 G risk alleles (OR 1.17, 95% CI. 1.03-1.34; p = 0.01), with cirrhosis (OR 1.58, 95% CI. 1.07-2.34; p = 0.02) and HCC (OR 1.98, 95% CI. 1.24-3.2; p = 0.004). Pro-NTS circulating levels were correlated with T2D (p = 0.005), BMI, (p = 0.04), age (p = 0.0016), lobular inflammation (p = 0.0025), fibrosis>2 (p < 0.0001), cirrhosis (p = 0.0009) and HCC (p < 0.0001) and more so after stratification for the NTS G allele. Transcriptomic data showed that hepatic NTS expression correlated with that of fibrogenic genes (p < 0.05). CONCLUSIONS: NTS rs1800832 variant is associated with advanced fibrosis and HCC in MAFLD patients likely affecting NTS protein activity. The rs6090453 NTSR1 gene variant synergizes with NTS rs1800832 mutation to promote liver damage. Prospective studies are necessary to confirm NTS role in liver disease progression.
BACKGROUND & AIMS:Neurotensin (NTS), a 13-aminoacid peptide localized in central nervous system and gastrointestinal tract, is involved in lipid metabolism and promotes various cancers onset mainly by binding to neurotensin receptor 1 (NTSR1). Increased plasma levels of pro-NTS, the stable NTS precursor, have been associated with type 2 diabetes (T2D), cardiovascular diseases and metabolic associated fatty liver disease (MAFLD). We aimed to evaluate 1) the impact of NTSrs1800832 and NTSR1rs6090453 genetic variants on liver damage in 1166 MAFLD European individuals, 2) the relation between NTS variant and circulating pro-NTS and 3) the hepatic NTS expression by RNAseq transcriptomic analysis in 125 bariatric patients. RESULTS: The NTSrs1800832 G allele was associated with hepatic fibrosis (OR 1.27, 95% confidence interval (CI). 1.02-1.58; p = 0.03), even more in carriers of both NTS and NTSR1 G risk alleles (OR 1.17, 95% CI. 1.03-1.34; p = 0.01), with cirrhosis (OR 1.58, 95% CI. 1.07-2.34; p = 0.02) and HCC (OR 1.98, 95% CI. 1.24-3.2; p = 0.004). Pro-NTS circulating levels were correlated with T2D (p = 0.005), BMI, (p = 0.04), age (p = 0.0016), lobular inflammation (p = 0.0025), fibrosis>2 (p < 0.0001), cirrhosis (p = 0.0009) and HCC (p < 0.0001) and more so after stratification for the NTS G allele. Transcriptomic data showed that hepatic NTS expression correlated with that of fibrogenic genes (p < 0.05). CONCLUSIONS:NTSrs1800832 variant is associated with advanced fibrosis and HCC in MAFLD patients likely affecting NTS protein activity. The rs6090453NTSR1 gene variant synergizes with NTSrs1800832 mutation to promote liver damage. Prospective studies are necessary to confirm NTS role in liver disease progression.
Authors: Beatriz Villar; Laia Bertran; Carmen Aguilar; Jessica Binetti; Salomé Martínez; Fàtima Sabench; Monica Real; David Riesco; Marta París; Daniel Del Castillo; Cristóbal Richart; Teresa Auguet Journal: Metabolites Date: 2021-06-10