REGULATION OF CHOLESTEROL BIOSYNTHESIS IN CULTURED CELLS OF NEURAL ORIGIN

Abstract

Biosynthesis of cholesterol, a major component of cellular membranes, is of particular importance in developing neural tissue. Because of the difficulties inherent in in vivo studies of whole brain, we have turned to cultured C-6 glial and neuroblastoma cells, which exhibit many properties of differentiating cells. Regulation of cholesterol biosynthesis and the major rate-controlling enzyme, HMG-CoA reductase, by the low density fraction (LDL) of serum lipoproteins (LP) was demonstrated. When glial cells were grown in LP-poor serum, a 22-fold increase in enzymatic activity was observed within 24 h. A qualitatively similar but quantitatively less impressive effect was noted in the neuronal cells. That the important component in LDL is cholesterol was shown by defining a 60% reduction in reductase activity in glial cells grown for 6 h in the presence of 50 μg/ml of pure cholesterol. Desmosterol was even more effective than cholesterol, producing an 80% reduction in activity at a concentration of only 10 μg/ml. Associated with the suppression of HMG-CoA reductase by LDL and by desmosterol was a stimulation of cholesterol ester synthesis. These observations suggest important roles in regulation of cholesterol synthesis for desmosterol and cholesterol esters, which are present in relatively high concentrations in brain only early in development. ------ The data have provided important information about the regulation of cholesterol biosynthesis in developing glial and neuronal cells and revealed differences in this regulation between the two cell types.

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