In Vivo and in Vitro Regulation of Sterol 27-Hydroxylase in the Liver during the Acute Phase Response

Abstract

The host response to infection is associated with several alterations in lipid metabolism that promote lipoprotein production. These changes can be reproduced by lipopolysaccharide (LPS) administration. LPS stimulates hepatic cholesterol synthesis and suppresses the conversion of cholesterol to bile acids. LPS down-regulates hepatic cholesterol 7␣-hydroxylase, the rate-limiting enzyme in the classic pathway of bile acid synthesis. We now demonstrate 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 hepatic sterol 27-hydroxylase mRNA levels by 75% compared with controls over a 24-h treatment period. LPS also decreases oxysterol 7␣-hydroxylase mRNA levels in mouse liver. In vitro studies in HepG2 cells demonstrate that tumor necrosis factor and interleukin (IL)-1 decrease sterol 27-hydroxylase 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 treatment also lowers hepatic sterol 27-hydroxylase mRNA levels in Syrian hamsters. Studies investigating the molecular mechanisms of LPS-induced decrease in sterol 27-hydroxylase show that LPS markedly decreases mRNA and protein levels of hepatocyte nuclear factor-1 (HNF-1), a transcription factor that regulates 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␣-hydroxylase, these data indicate that LPS suppresses both the classic and alternate pathways of bile acid synthesis. A decrease in bile acid synthesis in liver would reduce cholesterol catabolism and thereby contribute to the increase in hepatic lipoprotein production that is induced by LPS and cytokines.

Innate and acquired immunity intersect in a global view of the acute-phase response

“…3B). Together, these changes are consistent with a decrease in the consumption of cholesterol for bile acid synthesis, which could also contribute to increased serum cholesterol levels (27).…”

Mechanisms of Down-Regulation of CYP2E1 Expression by Inflammatory Cytokines in Rat Hepatoma Cells

“…However, the Fao cells could lack the dimerization cofactor HNF-1␣ (DcoH), which does not change DNA binding characteristics of HNF-1␣, but affects transcriptional activation (Hansen and Crabtree, 1993) or necessary coactivators could be absent. HNF-1␣ binding to its cognate response elements has previously been shown to be reduced by LPS and HNF-1␣ is probably involved in inflammatory repression of some genes such as ntcp and CYP27A (Trauner et al, 1998;Memon et al, 2001). Here, we show that IL-1␤ is able to decrease HNF-1␣ binding to the CYP2E1 promoter.…”

TNF‐α, a potent lipid metabolism regulator

“…74 Besides, the activities of mitochondrial sterol 27-hydroxylase and oxysterol 7a-hydroxylase, the rate-limiting enzymes in the alternative pathway of bile acid synthesis, were also down-regulated by TNF-a in human hepatoma cell lines. 75 Reverse cholesterol transport (RCT) plays a crucial role in preventing and reversing the development of hyperlipidemia and formation of atherosclerotic lesions. Several important proteins are involved in this process such as ABCA1, ATP binding cassette transporter G1 (ABCG1), cholesteryl ester transfer protein (CETP), lecithin cholesterol acyltransferase (LCAT), etc.…”