A role for thiamine in the regulation of fatty acid and cholesterol biosynthesis in cultured cells of neural origin.

Abstract

Abstract— Cultured glial (C‐6) and neuronal (neuroblastoma) cells were utilized to define the role of thiamine in the regulation of fatty acid and cholesterol biosynthesis. Glial cells subjected to thiamine deficiency exhibited rates of fatty acid synthesis that were only 13% of the rates in thiamine‐supple‐mented cells. The decrease in fatty acid synthetic rate was accompanied by a comparable decrease in the activities of fatty acid synthetase and acetyl‐CoA carboxylase, the two critical enzymes in the pathway. Immunochemical techniques demonstrated that the decrease in activity of fatty acid synthetase reflected a decrease in enzyme content and that this change in content was caused by a decrease in enzyme synthesis. The disturbance of fatty acid synthesis was exquisitely sensitive to thiamine–i.e. marked improvement was evident within hours of replenishment with only 0.01 μ/ml of thiamine. Total recovery occurred in 1–2 days. Thiamine‐deficient glia also exhibited reduced rates of cholesterol biosynthesis, i.e. 60% of the rates in thiamine‐supplemented cells. This effect was accompanied by a comparable reduction in activity of 3‐hydroxy‐3‐methylglutaryl‐CoA (HMG‐CoA) reductase, the rate‐limiting step in cholesterol biosynthesis. Unlike the glial cells, the neuronal cells exhibited either no or only a slight reduction in lipid synthesis under similar conditions of thiamine deficiency.The data have important implications for the genesis of the neuropathology in states of altered thiamine homeostasis and for the mechanisms of regulation of lipid synthesis.