Tellurium-induced alterations in 3-hydroxy-3-methylglutaryl-CoA reductase gene expression and enzyme activity: differential effects in sciatic nerve and liver suggest tissue-specific regulation of cholesterol synthesis.
The demyelination of peripheral nerves that results from exposure of developing rats to tellurium is due to inhibition of squalene epoxidase, a step in cholesterol biosynthesis. In sciatic nerve, cholesterol synthesis is greatly depressed, whereas in liver, some compensatory mechanism maintains normal levels of cholesterol synthesis. This tissue specificity was further explored by examining, in various tissues, gene expression and enzyme activity of 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. Exposure to tellurium resulted in pronounced increases in both message levels and enzyme activity in liver, the expected result consequent to up-regulation of this enzyme in response to decreasing levels of intracellular sterols. In contrast to liver, levels of mRNA and enzyme activity in sciatic nerve were both decreased during the tellurium-induced demyelinating period. The temporal pattern of changes in 3-hydroxy-3-methylglutaryl-CoA reductase message levels in sciatic nerve seen following exposure to tellurium was similar to the down-regulation seen for mRNA specific for PNS myelin proteins. Possible mechanisms for differential control of cholesterol biosynthesis in sciatic nerve and liver are discussed.
Toews
A D
AD
Department of Biochemistry, University of North Carolina, Chapel Hill 27599-7250.
Goodrum
J F
JF
Lee
S Y
SY
Eckermann
C
C
Morell
P
P
D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis*; D015870:Gene Expression / Q000187:drug effects*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains; D012584:Sciatic Nerve / Q000201:enzymology*; D013691:Tellurium / Q000494:pharmacology*
D012333:RNA, Messenger; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D013691:Tellurium