DECREASED CHOLESTEROL EFFLUX FROM FIBROBLASTS OF A PATIENT WITHOUT TANGIER-DISEASE, BUT WITH MARKEDLY REDUCED HIGH-DENSITY-LIPOPROTEIN CHOLESTEROL LEVELS

A 51-yr-old woman without clinical evidence of Tangier disease, but wi th an extremely low high density lipoprotein (HDL) cholesterol level, was studied. No defect in the major structural protein of HDL, apolipo protein AI (apo AI), was detected. A preponderance of small HDL partic les in the patient's plasma suggested defective uptake of cellular cho lesterol. Efflux of [H-3]cholesterol from patient fibroblasts to norma l apo AI was decreased 50%. Cholesterol efflux to HDL was also decreas ed, but efflux to trypsin-modified HDL was not. The patient's cells pa rtitioned more exogenously provided [H-3]cholesterol into free cholest erol and synthesized greater amounts of phosphatidylcholine than did n ormal or Tangier fibroblasts. Her fibroblasts did not differ from norm al fibroblasts in sterol synthesis rate, cellular cholesterol and chol esterol ester content, or incorporation of oleate into cholesterol est er. The data indicate the presence of a defect in apolipoprotein-depen dent cellular cholesterol efflux that differs from that seen in Tangie r disease. These findings are the first evidence that other low HDL ch olesterol syndromes, besides Tangier disease, may also be associated w ith cholesterol efflux abnormalities. The identification of mutant gen es responsible for apolipoprotein-mediated efflux abnormalities should provide valuable insights into cellular mechanisms involved in the re verse cholesterol transport pathway.