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Journal of Lipid Research, Vol 37, 223-228, Copyright © 1996 by Lipid Research, Inc.
KR Feingold, DK Spady, AS Pollock, AH Moser and C Grunfeld
Endotoxin (LPS) and cytokines increase cholesterol synthesis and the
secretion of lipoproteins by the liver in rodents resulting in
hypercholesterolemia. Cholesterol 7 alpha-hydroxylase (CAH) is the rate-
limiting enzyme in the conversion of cholesterol to bile acids in the
liver, the major regulated pathway by which cholesterol is eliminated from
the body. Decreases in CAH would increase the quantity of cholesterol
available for lipoprotein production. In the present study, we demonstrate
that LPS, TNF, or IL-1 administration to Syrian hamsters produces a marked
decrease in the levels of CAH mRNA in the liver. This marked decrease
occurred even when the basal level of CAH expression was increased by
feeding the bile acid sequestrant, colestipol. Additionally, a marked
decrease was also observed when the animals were fed a cholesterol-enriched
diet. Moreover, the decrease in CAH mRNA occurred very rapidly (decreased
66% by 90 min after LPS administration) and required relatively small doses
of LPS (100 ng/100 g body weight). Lastly, the decrease in mRNA levels was
accompanied by a decrease in CAH activity. This decrease in CAH could
contribute to the increase in hepatic lipoprotein production induced by LPS
and cytokines. CAH can be added to the growing list of proteins that
regulate lipid metabolism and that are altered during the acute phase
response.
ARTICLES
Endotoxin, TNF, and IL-1 decrease cholesterol 7 alpha-hydroxylase mRNA levels and activity
Department of Medicine, University of California, San Francisco 94121, USA.
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