Neurotensin receptor-1 antagonist SR48692 modulation of high-fat diet–induced pathogenesis of NAFLD in mice

Abstract

This study investigates the efficacy of the antagonist of neurotensin receptor-1 (NTSR1) SR48692 in modulating the high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD). HFD increases NTS secretion, which enhances fat absorption from the gastrointestinal tract (GIT) via receptors NTSR1/NTSR2/NTSR3. Absorbed fat from the GIT via hepatic-portal system reaches the liver, where it gets accumulated to cause NAFLD. Swiss albino mice (8 weeks) were maintained in two batches fed standard diet (SD) and HFD for 4 weeks, then divided into six groups: Group I (SD) and Group II (HFD) administered intraperitoneally 0.9% saline (vehicle), Group III: low dose of antagonist (100 µg kg⁻¹ bw: HFD+SR48692_L), Group IV: high dose (400 µg kg⁻¹ bw: HFD+SR48692_H), Group V (SD+SR48692_L), and Group VI (SD+SR48692_H). SR48692_L treatment in HFD-fed mice showed partial efficacy in preventing lipid absorption and reducing oxidative stress, as reflected in histology and plasma transaminases. Contrarily, with SR48692_H dose, the effects were detrimental. Involvement of other signaling pathways (NTS-NTSR2, NTS-NTSR3) in lipid absorption might be the reason of partial efficacy. The adverse effects with the SR48692_H might be due to the differential dose–response effect of the antagonist.

Practical Application: HFD-induced hyperlipidemia and NAFLD are linked to enhanced NTS secretion. As NTS enhances fat absorption, blocking its receptors with antagonists might provide efficacy against HFD-induced NAFLD. This study with NTSR1 antagonist SR48692 provides some evidence of its in preventing hyperlipidemia; further studies targeting other receptors (NTSR2, NTSR3) are essential for understanding the therapeutic efficacy of the NTS antagonists for NAFLD.