AJP - Regulatory, Integrative and Comparative Physiology, Vol 257, Issue 3 618-R625, Copyright © 1989 by American Physiological Society
Physiological role of HMG-CoA reductase in regulating egg production by Schistosoma mansoni
E. A. Vandewaa, G. Mills, G. Z. Chen, L. A. Foster and J. L. Bennett
Department of Microbiology, Michigan State University, East Lansing 48824.
Pathological lesions observed in humans infected with Schistosoma mansoni
are due to the eggs produced by the female parasite. Mevinolin, a potent
inhibitor of the enzyme hydroxymethylglutaryl-CoA (HMG-CoA) reductase,
blocks egg production by this parasite. In this report, we demonstrate that
cholesterol precursors, mevalonate and farnesol, stimulate egg production
by the female parasite and that these precursors can reverse the
mevinolin-induced inhibition of egg production. Because the parasite cannot
synthesize cholesterol, we incubated parasites in a culture media
containing radiolabeled acetate with and without mevinolin. We isolated
nonsterol lipids from the parasite and observed that mevinolin dramatically
reduced the conversion of acetate into the polyisoprenoid (dolichols)
lipids of the parasite. Dolichols and other nonsterol lipids did not
stimulate egg production. HMG-CoA reductase activity was observed in
homogenates of the parasite and was inhibited by mevinolin (Ki = 52 nM),
but its activity was tripled when the parasite was chronically exposed to
low doses of the drug. Parasites with increased reductase activity produced
five to six times more eggs. Lastly, chronic administration of large doses
of mevinolin to infected mice resulted in a marked reduction of the
pathology associated with the infection. These results suggest that egg
production in S. mansoni is associated with the parasite's HMG-CoA
reductase activity and that a nonsterol lipid produced in the biochemical
pathway regulated by this enzyme stimulates egg production.
