Mechanisms of Lipid Metabolism Disorders in Experimental Non-Alcoholic Fatty Liver Disease: The Role of LDLR, LOX-1, ApoE and LRP1
Background: Non-alcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disorder and is closely linked to insulin resistance and the metabolic syndrome. Beyond the accumulation of triacylglycerides (TAG), disturbed hepatic cholesterol handling — mediated by the low-density lipoprotein receptor (LDLR), the lectin-like oxidised LDL receptor-1 (LOX-1), apolipoprotein E (ApoE) and LDL receptor-related protein 1 (LRP1) — has been proposed as a central pathogenetic mechanism. Objective: To evaluate the serum protein factors involved in triacylglyceride and cholesterol metabolism during the stepwise development of experimental fatty hepatosis. Methods: Fifty outbred white rats weighing 150–180 g were studied. Eight animals formed the intact group and received a standard vivarium diet; 42 animals received a high-fat diet (cow lard) supplemented with a 10% glucose–fructose solution (1:1) for 5 months. Serum was examined at 2, 3, 4 and 5 months. Total protein, albumin, bilirubin, urea, glucose, TAG, total cholesterol (TC) and cholesterol in very-low-density (VLDL-C), low-density (LDL-C) and high-density (HDL-C) lipoproteins were measured, and the atherogenic index (AI) together with ALT, AST, GGT and ALP activities were determined. Insulin, LDLR, LOX-1, ApoE and LRP1 were measured by sandwich enzyme-linked immunosorbent assay. HOMA-IR, the TAG/HDL-C ratio and the metabolic index (MI) were calculated. Results: High-calorie feeding produced a progressive increase in serum TAG (up to 2.11-fold) and TC (up to 1.93-fold), a rise in VLDL-C (up to 2.96-fold) and LDL-C (up to 4.19-fold) and a fall in HDL-C, with the AI increasing from 0.66 ± 0.03 to 3.66 ± 0.28 (5.54-fold; P < 0.001). Glucose rose 1.49-fold, insulin 2.73-fold and HOMA-IR 3.13-fold by month 5. Serum LDLR fell progressively (2.41-, 3.34- and 4.89-fold at 2, 3 and 4 months, with partial recovery to a 3.61-fold reduction at 5 months), whereas LOX-1 rose (1.63-, 2.03-, 2.18- and 1.94-fold). ApoE showed a biphasic pattern: a 1.52-fold decrease at 2 months followed by a rise above intact values at 4 (1.32-fold) and 5 months (1.23-fold). LRP1 was unchanged at 2 months and then decreased by 1.25-, 1.40- and 1.43-fold. Conclusion: Prolonged high-calorie feeding reproduces fatty hepatosis accompanied by the full biochemical picture of the metabolic syndrome. The progressive decline of LDLR together with a rise in LOX-1, a biphasic ApoE response and a gradual reduction of LRP1 indicate a dysregulation of receptor-mediated hepatic cholesterol handling and suggest that these proteins merit further evaluation as early markers of fatty hepatosis.