Low density lipoprotein receptor activity on skin fibroblasts from rhesus monkeys with diet-induced or spontaneous hypercholesterolemia.

The purpose of this study was to evaluate low density lipoprotein (LDL) receptor activity on skin fibroblasts from rhesus monkeys with either spontaneous or dietinduced hypercholesterolemia in order to determine whether a defect in LDL receptor function was associated with the hyperbetalipoproteinemia in either of these conditions. This was of particular interest in the spontaneously hypercholesterolemic animals since animals with this genetically mediated disorder have many of the phenotypic characteristics of familial hypercholesterolemia in man. Skin fibroblasts were grown from two spontaneously hypercholesterolemic rhesus monkeys that maintained plasma cholesterol concentrations of >700 mg/dl while consuming a cholesterol-free diet. Control monkeys were normocholesterolemic (plasma cholesterol concentrations t150 mg/ dl) while consuming a cholesterol-free diet, but were either hypoor hyperresponsive to dietary cholesterol with plasma cholesterol concentrations ranging from 250 to 1000 mg/dl. Skin fibroblasts from all spontaneously hypercholesterolemic and control animals bound, internalized, and degraded lZ6I-LDL normally. Cells from spontaneously hypercholesterolemic animals were larger and expressed more LDL receptors per cell when maximally stimulated than did normal cells. Likewise, differences in LDL receptor function were not correlated with hypoor hyperresponsiveness to dietary cholesterol in control animals. The LDL receptors also functioned normally in delivering cholesterol to cells from all but one of the spontaneously cholesterolemic animals as seen by the suppression of 3-hydroxy3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) activity. Cells from this animal (No. 1108) showed a relative defect in regulation of HMG-CoA reductase activity, but no obvious relationship of this defect to an explanation of the spontaneous hypercholesterolemia was found. Consequently, spontaneous hypercholesterolemia, in the two rhesus monkeys studied here, even though having many of the phenotypic characteristics of familial hypercholesterolemia in human beings, was not associated with a similar defect in LDL receptor function.