Experimental Models of Metabolic Dysfunction-Associated Steatotic Liver Disease: A Comparative Analysis of a Choline-Deficient and Cholesterol-Enriched Diet in Rats

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a widespread pathology requiring adequate preclinical models for studying pathogenesis and evaluating therapeutic and preventive agents. This study compared differential markers of MASLD pathogenesis in rats using two distinct dietary models: a choline-deficient high-fat diet (HFD-CD) and a cholesterol-enriched high-fat diet (HFD+CHOL). Male Wistar rats were fed either a control AIN93M diet, HFD-CD (40% fat, 20% fructose, and choline deficiency), or HFD+CHOL (40% fat, 20% fructose, and 1% cholesterol) for 56 days. Comprehensive assessment included phenotypic, biochemical, hematological, histomorphological parameters, oxidative stress markers, hepatocyte apoptosis, cytokine levels, and hepatic gene expression. HFD-CD induced steatosis with moderate insulin resistance, increased malondialdehyde levels, and suppressed Acaca, Scd and ChREBP gene expression. In contrast, HFD+CHOL caused macrovesicular steatosis, inflammation, early fibrosis, atherogenic dyslipidemia, intrahepatic cholesterol accumulation, hepatocyte apoptosis, upregulated Srebf1, Cyp7a1, and Nfkb1 expression, and activated Nrf2-dependent antioxidant responses. HFD-CD and HFD+CHOL induce two pathogenetically distinct MASLD phenotypes. The HFD-CD model, characterized by steatosis and oxidative stress without pronounced inflammation or fibrosis, is preferable for studying the preventive potential of bioactive food compounds. Conversely, the HFD+CHOL model with inflammatory and fibrotic components is more suitable for evaluating therapeutic agents aimed at mitigating inflammation, restoring cholesterol homeostasis, and attenuating fibrosis.