TY - JOUR
T1 - Neurotensin up-regulation is associated with advanced fibrosis and hepatocellular carcinoma in patients with MAFLD
AU - Dongiovanni, Paola
AU - Meroni, Marica
AU - Petta, Salvatore
AU - Longo, Miriam
AU - Alisi, Anna
AU - Soardo, Giorgio
AU - Valenti, Luca
AU - Miele, Luca
AU - Grimaudo, Stefania
AU - Pennisi, Grazia
AU - Antonio, Grieco
AU - Consonni, Dario
AU - Fargion, Silvia
AU - Fracanzani, Anna Ludovica
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - Biomarker
KW - Genetic variants
KW - Lipid metabolism
KW - Liver damage
KW - Therapeutic target
KW - Biomarker
KW - Genetic variants
KW - Lipid metabolism
KW - Liver damage
KW - Therapeutic target
UR - http://hdl.handle.net/10807/219757
U2 - 10.1016/j.bbalip.2020.158765
DO - 10.1016/j.bbalip.2020.158765
M3 - Article
SN - 1388-1981
VL - 1865
SP - 158765-N/A
JO - BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
JF - BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
ER -