Journal of Lipid Research, Vol 37, 2502-2509, Copyright © 1996 by Lipid Research, Inc.
Tissue-specific coordinate regulation of enzymes of cholesterol biosynthesis: sciatic nerve versus liver
AD Toews, H Jurevics, J Hostettler, EB Roe and P Morell
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill 27599-7250, USA.
Exposure of weanling rats to a diet containing the element tellurium
results in specific inhibition of squalene epoxidase, an obligate enzyme in
cholesterol biosynthesis. Liver responds to the resulting intracellular
sterol deficit by up-regulating, in parallel and to the same extent,
expression of mRNA for squalene epoxidase and for HMG-CoA reductase, the
major rate-limiting enzyme in the pathway. This increased mRNA expression,
coupled with additional translational and posttranslational activation of
the pathway allows normal levels of cholesterol synthesis in liver despite
tellurium-induced inhibition of squalene epoxidase. The response to
tellurium challenge in sciatic nerve is very different. In this tissue,
cholesterol synthesis is prominent because of the large amount of
cholesterol required for synthesis and maintenance of myelin. Although
nerve shows an initial (at 1 day) up-regulation of mRNA expression for both
enzymes in response to tellurium exposure, this is followed quickly by
parallel down-regulation of both enzymes, in concert with down-regulation
of mRNA expression for myelin proteins. We suggest that the tellurium-
induced deficit in sterols leads to a coordinate down-regulation of
synthesis of myelin components. The initial early up-regulation of
cholesterol biosynthesis in sciatic nerve due to the cholesterol deficit is
countered by down-regulation which is coordinated with overall control of
the program of myelin assembly. This tissue-specific control of cholesterol
synthesis in sciatic nerve is a point of vulnerability to toxicants, and
may be related to the need for coordinate synthesis of all components of
myelin.
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