Hepatic LOX-1 Downregulation Is Associated with Metabolic Dysfunction-Associated Steatotic Liver Disease Improvement in High-Fat Diet-Fed Rats: Protective Role of Aerobic <i>Exercise</i>

Abstract

Background: Changes in dietary composition and increased dietary fat intake contribute to hypertriglyceridemia and subsequent dyslipidemia, thereby exacerbating chronic, progressive metaflammatory conditions. These effects are mediated by impaired triglyceride clearance and reduced lipolytic enzyme activity, ultimately leading to deterioration of liver function and metabolic dysfunction-associated steatotic liver disease (MASLD). Objectives: This study aimed to investigate how moderate-intensity swimming exercise modulates high-fat diet-induced structural changes and metaflammation in the liver, with a particular focus on the role of the lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1). Methods: Thirty-two male Wistar rats were randomly allocated to four groups (n = 8/group): Control (standard diet, sedentary), Exercise (standard diet plus exercise), high-fat diet (HFD; high-fat diet, sedentary), and Exercise plus HFD (high-fat diet plus exercise). Rats in the exercise groups swam freely for 1 hour/day, 5 days/week, for 8 weeks. Approximately 48 hours after completion of the training protocol, blood samples were collected to assess the lipid profile, glucose, and nitrogen oxides (NOx). Liver tissue was also isolated and evaluated using histological and immunohistochemical methods. Results: Chronic HFD consumption significantly increased body weight, serum cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), glucose, and NOx levels, as well as tissue LOX-1 and interleukin 6 (IL-6) levels, and distorted histopathological characteristics compared with the Control group (P < 0.001). Aerobic swimming training significantly reversed HFD-induced weight gain and lipid profile upregulation and modulated oxidative stress by downregulating hepatic LOX-1 levels (P < 0.05), which was associated with reduced IL-6 protein expression and improved histological features. Conclusions: Chronic moderate aerobic exercise may protect against HFD-induced MASLD by reducing inflammatory stress and is associated with the suppression of MASLD development. These findings identify LOX-1 as a potential biomarker and suggest that exercise-mediated LOX-1 downregulation may represent a therapeutic target; however, further mechanistic studies are needed to establish causality.