Hypoalbuminemia is accompanied by hypercholesterolemia in both nephrotic syndrome and hereditary analbuminemia. Hypercholesterolemia is more severe in the female than in the male Nagase analbuminemic rats (NAR). The sex difference in plasma cholesterol diminishes after ovariectomy (OVX) and reappears after estrogen replacement in the NAR. The molecular mechanism responsible for the sex difference in severity of hypercholesterolemia in NAR is not known and was investigated here. To this end, hepatic hydroxylmethylglutaryl (HMG)-CoA reductase, cholesterol 7␣-hydroxylase, and LDL receptor were determined in male, female, and OVX female NAR and Sprague-Dawley (SD) rats. Plasma cholesterol, triglycerides, and hepatic HMG-CoA reductase activities were greater in both female and male NAR than in SD rats. This was coupled with upregulation of cholesterol 7␣-hydroxylase in both male and female NAR compared with SD controls. LDL receptor in male NAR was similar to that in male SD rats but was significantly reduced in female NAR. OVX partially, but significantly, reduced plasma cholesterol and triglyceride levels in female NAR. This was coupled with a significant rise in hepatic cholesterol 7␣-hydroxylase and a modest increase in hepatic LDL receptor. In contrast, OVX resulted in a mild elevation of plasma cholesterol and no significant changes in total hepatic HMG-CoA reductase, cholesterol 7␣-hydroxylase, or LDL receptor in female SD rats. Thus the greater severity of hypercholesterolemia in the female NAR appears to be due, in part, to a combination of the constrained compensatory upregulation of cholesterol 7␣-hydroxylase and LDL receptor deficiency.hyperlipidemia; hypercholesterolemia; nephrotic syndrome; proteinuria; low-density lipoprotein; hydroxymethylglutaryl-CoA reductase; bile acids HEAVY GLOMERULAR PROTEINURIA (nephrotic syndrome) results in hypoalbuminemia, diminished plasma oncotic pressure, and a marked rise in plasma total cholesterol concentration (14). Hypercholesterolemia, albeit less severe, is also present the Nagase rats (2,3,11,13,14) and humans (1) with hereditary analbuminemia in whom proteinuria is absent. These observations suggest that hypoalbuminemia, per se, can raise plasma cholesterol concentration. Hypercholesterolemia is more severe in the female Nagase analbuminemic rat (NAR) than in the male NAR (11,14). The difference in plasma cholesterol concentration between the male and female NAR diminishes after ovariectomy (OVX) and reappears with estrogen replacement (7-10). Similarly, estrogen administration aggravates hypercholesterolemia in rats with adriamycin-induced nephrotic syndrome, wherein hypoalbuminemia is due to proteinuria (4). In contrast, orchiectomy does not change plasma cholesterol in the male NAR (8). These observations suggest that the effect of hypoalbuminemia on plasma cholesterol concentration is amplified by an ovarian factor, most likely estrogen.In an earlier study (6), we found a significant increase in extrahepatic cholesterol synthesis in NAR. In a subsequent study...