CONTROL OF CHOLESTEROL-BIOSYNTHESIS IN SCHWANN-CELLS

Cholesterol accounts for over one-fourth of total myelin lipids. We fo und that, during development of the rat sciatic nerve, expression of m RNA for hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, the rate -limiting enzyme in cholesterol biosynthesis, was upregulated in paral lel with mRNA for P-0, the major structural protein of PNS myelin, and with ceramide galactosyltransferase (CGT), the rate-limiting enzyme i n cerebroside biosynthesis, To help establish the nature of this coord inate regulation of myelin-related genes, we examined their steady-sta te mRNA levels in cultured primary Schwann cells. We also assayed synt hesis of cholesterol and cerebroside to distinguish how much control o f synthetic activity for these two myelin lipids involved mRNA levels for HMG-CoA reductase and CGT, and how much involved post-mRNA control mechanisms. Addition of forskolin to cells cultured in media suppleme nted with normal calf serum resulted in up-regulation of P-0 and CGT m RNA expression and cerebroside synthesis, without corresponding increa ses in HMG-CoA reductase mRNA or cholesterol synthesis. Cholesterol sy nthesis increased approximately threefold in Schwann cells cultured wi th lipoprotein-deficient serum, without any increase in HMG-CoA reduct ase mRNA, Furthermore, addition of either serum lipoproteins or 25-hyd roxycholesterol decreased cholesterol synthesis without altering HMG-C oA reductase mRNA levels. We conclude that, as in other tissues, chole sterol synthesis in Schwann cells is regulated primarily by intracellu lar sterol levels. Much of this regulation occurs at posttranscription al levels. Thus, the in vivo coordinate up-regulation of HMG-CoA reduc tase gene expression in myelinating Schwann cells is secondary to intr acellular depletion of cholesterol, as it is compartmentalized within the myelin. It is probably not due to coordinate control at the level of mRNA expression.