Ra. Memon et al., In vivo and in vitro regulation of sterol 27-hydroxylase in the liver during the acute phase response - Potential role of hepatocyte nuclear factor-1, J BIOL CHEM, 276(32), 2001, pp. 30118-30126
The host response to infection is associated with several alterations in li
pid metabolism that promote lipoprotein production. These changes can be re
produced by lipopolysaccharide (LPS) administration. LPS stimulates hepatic
cholesterol synthesis and suppresses the conversion of cholesterol to bile
acids. LPS down-regulates hepatic cholesterol 7 alpha -hydroxylase, the ra
te-limiting enzyme in the classic pathway of bile acid synthesis. We now de
monstrate that LPS markedly decreases the activity of sterol 27-hydroxylase
, the rate-limiting enzyme in the alternate pathway of bile acid synthesis,
in the liver of Syrian hamsters. Moreover, LPS progressively decreases hep
atic sterol 27-hydroxylase mRNA levels by 75% compared with controls over a
24-h treatment period. LPS also decreases oxysterol 7 alpha -hydroxylase m
RNA levels in mouse liver. In vitro studies in HepG2 cells demonstrate that
tumor necrosis factor and interleukin (IL)-1 decrease sterol 27-hydroxylas
e MRNA levels by 48 and 80%, respectively, whereas IL-6 has no such effect.
The IL-1-induced decrease in sterol 27-hydroxylase mRNA expression occurs
early, is sustained for 48 h, and requires very low doses. In vivo IL-1 tre
atment also lowers hepatic sterol 27-hydroxylase mRNA levels in Syrian hams
ters. Studies investigating the molecular mechanisms of LPS-induced decreas
e in sterol 27-hydroxylase show that LPS markedly decreases mRNA and protei
n levels of hepatocyte nuclear factor-1 a transcription factor that regulat
es sterol 27-hydroxylase, in the liver. Moreover, LPS decreases the binding
activity of HNF-1 by 70% in nuclear extracts in hamster liver, suggesting
that LPS may down-regulate sterol 27-hydroxylase by decreasing the binding
of HNF-1 to its promoter. Coupled with our earlier studies on cholesterol 7
alpha -hydroxylase, these data indicate that LPS suppresses both the class
ic and alternate pathways of bile acid synthesis. A decrease in bile acid s
ynthesis mi liver would reduce cholesterol catabolism and thereby contribut
e to the increase in hepatic lipoprotein production that is induced by LPS
and cytokines.