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

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 mu g kg-1 bw: HFD+SR48692L), Group IV: high dose (400 mu g kg-1 bw: HFD+SR48692H), Group V (SD+SR48692L), and Group VI (SD+SR48692H). SR48692L 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 SR48692H 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 SR48692H 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. Graphical Abstract: The present study focused on the ameliorative effect of SR48692 in HFD-induced NAFLD in mice. Consumption of HFD impaired plasma lipid profiles, antioxidant defense system, as well as histopathological alterations in liver. The co-treatment with a low dose of SR48692 (HFD+SR48692L) reverts the studied parameters, which suggests its therapeutic approach for NAFLD. image