Neurotensin up-regulation is associated with advanced fibrosis and hepatocellular carcinoma in patients with MAFLD

Paola Dongiovanni, Marica Meroni, Salvatore Petta, Miriam Longo, Anna Alisi, Giorgio Soardo, Luca Valenti, Luca Miele, Stefania Grimaudo, Grazia Pennisi, Grieco Antonio, Dario Consonni, Silvia Fargion, Anna Ludovica Fracanzani

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number158765
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1865
Issue number10
DOIs
Publication statusPublished - Oct 2020

Keywords

  • Biomarker
  • Genetic variants
  • Lipid metabolism
  • Liver damage
  • Therapeutic target

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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