Comparative Therapeutic Effects of LPS-Primed MSC-Derived Exosomes and Saroglitazar in a Wistar Rat Model of Non-Alcoholic Steatohepatitis via AMPK/ACC Signaling Modulation

Abstract

Background: Nonalcoholic fatty liver disease and its inflammatory, progressive form, nonalcoholic steatohepatitis (NAFLD/NASH), represent a continuum of metabolic liver pathology characterized by steatosis and hepatic inflammation. Despite its rising global prevalence, effective disease-modifying therapies remain limited. Accumulating evidence indicates that mesenchymal stromal cell-derived exosomes (MSC-Exo) represent a novel and potentially effective cell-free therapeutic option for metabolic liver disorders. Objectives: The current study aimed to comprehensively evaluate the therapeutic efficacy of exosomes isolated from lipopolysaccharide (LPS)-conditioned MSCs in ameliorating NASH induced by a high-fat diet, with a specific focus on modulating the AMPK/ACC signaling pathway. Methods: In this experimental study, male Wistar rats were fed a high-fat diet for eight weeks to induce NASH. Forty rats were allocated into five groups (n = 8/group), including a control group and four HFD-fed groups. From week 8, animals received saroglitazar or exosomes derived from either naïve MSCs or LPS-primed MSCs for six weeks via intravenous (tail vein) injection (150 µg protein). Exosomes were characterized by transmission electron microscopy (TEM), particle size analysis, and Western blotting for CD9 and CD81. Body and liver weight, hepatic triglyceride levels, liver function markers, fibrosis-related genes, and collagen deposition were evaluated. Gene expression analysis of lipid metabolism, inflammation, fibrosis, and AMPK/ACC signaling was performed using qRT-PCR. Results: Treatment with exosomes derived from LPS-primed MSCs significantly attenuated HFD-induced hepatic steatosis, as evidenced by reduced liver weight and hepatic triglyceride accumulation (P < 0.01 - 0.001). These effects were associated with activation of the AMPK/ACC signaling pathway, suppression of lipogenic gene expression, and improved metabolic homeostasis. Furthermore, LPS-primed MSC exosomes significantly improved serum lipid parameters and reduced ALT and AST levels (P < 0.05 - 0.001). A marked reduction in pro-inflammatory mediators and hepatic collagen deposition was also observed compared with untreated and naïve MSC exosome-treated groups. Conclusions: Exosomes derived from LPS-primed MSCs exert significant hepatoprotective and antifibrotic effects in HFD-induced NASH. These beneficial effects are mediated, at least in part, through activation of the AMPK/ACC signaling pathway and suppression of inflammatory and fibrogenic responses. Collectively, these findings suggest that LPS-primed MSC-derived exosomes may represent a promising cell-free therapeutic strategy for the management of NASH.