The metabolic defect in patients with Types C and D Niemann-Pick disease has been shown to be due to abnormal intracellular cholesterol homeostasis. The molecular lesion in these disorders results in: (1) failure to down-regulate LDL receptors on cell membranes; (2) lack of down-regulation of HMGCoA reductase, a key enzyme in cholesterol biosynthesis; and (3) inability to up-regulate acyl cholesterol acyl CoA transferase, the enzyme that catalyzes the esterification of intracellular cholesterol. Tests have been developed and introduced into medical practice for the diagnosis of Types C and D Niemann-Pick disease and the identification of heterozygotes, and the prenatal diagnosis of these conditions. We have observed that the addition of progesterone to cultured skin fibroblasts derived from normal individuals reversibly blocks the intracellular translocation of cholesterol that is similar to that in cells from patients with Type C Niemann-Pick disease (NPC). We also found that naturally occurring organic amines such as stearylamine and sphingosine elicit effects that closely mimic the abnormal cell biology of NPC. Moreover, we discovered that the quantity of sphinganine, a precursor of sphingosine, is greatly increased in the liver of the murine analogue of human NPC. These findings provide considerable additional insight into the pathogenesis of this neurometabolic disorder.
