Nephrotic syndrome (NS) is invariably associated with elevation of plasma total and LDL cholesterol concentrations. The present study was carried out to test the hypothesis that nephrotic LDL hypercholesterolemia is, in part, due to acquired LDL receptor (LDLR) deficiency. To this end, hepatic LDLR mRNA (Northern blot analysis) and protein mass (Western blot analysis) were measured longitudinally before and during the course of puromycin-induced NS. In addition, the rate of LDLR gene transcription by isolated hepatic nuclei was determined using nuclear run-on assay. Hepatic LDLR mRNA remained virtually unchanged during the 30-day course of the study period. However, after an insignificant rise on day 5, LDLR protein mass gradually declined to a level which was significantly below the baseline values (P < 0.05 ANOVA). This was accompanied by a normal rate of LDLR mRNA synthesis excluding impaired gene transcription as a cause. The fall in hepatic LDLR protein was associated with a marked rise in plasma total and LDL cholesterol concentrations but no rise in hepatic tissue cholesterol concentration. The latter observation is indicative of impaired hepatic cholesterol uptake and provides functional evidence for the demonstrated acquired LDLR deficiency in the NS animals. Likewise, our findings elucidate the molecular basis of the previously reported impaired LDL clearance in NS. In conclusion, severe hypercholesterolemia in rats with experimental NS is associated with and perhaps, in part, is due to down-regulation of LDL receptor expression.