Endotoxin (LPS), by raising the levels of
cytokines, markedly influences lipid metabolism. To clarify the molecular mechanism of this effect, we examined the action of
endotoxin in vitro and in vivo on the regulation of
sterol regulatory
element binding protein-1 (SREBP-1). In HepG2 cells stimulated with LPS, a dose-dependent increase in the level of the mature form of SREBP-1 was observed. For in vivo studies,
endotoxin was administered intraperitoneally to CD1 mice fed with a standard or a
cholesterol-enriched diet to increase the basal levels of circulating and liver
cholesterol.
Endotoxin raised
cholesterol levels and stimulated the maturation of hepatic SREBP-1 in both normal and
cholesterol-fed mice, indicating that the lipogenic effect of LPS was independent of endogenous
sterol levels. To assess whether the lipogenic effect of
endotoxin was linked to
cytokine production, we administered LPS to C57Bl/6J
endotoxin-sensitive and to C3H/HeJ
endotoxin-resistant mice, which do not produce
tumor necrosis factor in response to LPS. Significant induction of
cholesterol levels and SREBP-1 activation was observed only in C57Bl/6J mice, indicating that
cytokine production is crucial for the regulation of SREBP-1, and that the transcriptional activation of
cholesterol biosynthesis may be part of the
acute-phase response.