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Journal of Lipid Research, Vol. 43, 952-959, June 2002
Copyright © 2002 by Lipid Research, Inc.

Bacterial lipopolysaccharide induces expression of ABCA1 but not ABCG1 via an LXR-independent pathway

Rebecca Kaplan^*, Xiaodong Gan^*, John G. Menke, Samuel D. Wright^* and Tian-Quan Cai^1,*

^* Departments of Atherosclerosis and Endocrinology, Merck Research Laboratories, Rahway, New Jersey 07065
Molecular Endocrinology, Merck Research Laboratories, Rahway, New Jersey 07065

¹ To whom correspondence should be addressed. e-mail: tianquan_cai{at}merck.com

Two ATP-binding cassette transporter proteins, ABCA1 and ABCG1, may mediate an active efflux of cellular cholesterol and phospholipids. They are ubiquitously expressed and are subject to regulation by cholesterol loading or by treatment with agents that activate the nuclear hormone receptor LXR. Earlier studies in both primates and non-primates reported that treatment with endotoxin (bacterial lipopolysaccharide, LPS) reduces plasma levels of HDL cholesterol. To determine if such HDL reduction correlates with a change in ABCA1 or ABCG1 expression, their expressions were measured in THP-1 monocytes and mice treated with LPS. LPS treatment leads to a rapid, dose-dependent increase of ABCA1 but not ABCG1 mRNA expression. Analysis of mouse livers showed that LPS treatment decreases expression of CYP7A, another target gene of LXR. When THP-1 cells were transfected with the ABCA1 promoter construct (-928 to +101 bp), promoter activity was significantly increased by treatment of 22(R)-hydroxycholesterol but not by LPS. Together, these studies show that LPS regulates ABCA1 expression through an LXR-independent mechanism. Further studies showed that treatment with Rhodobacter sphaeroiders LPS, an LPS antagonist, or PD169316, a specific p38 MAP kinase inhibitor, prevented the induction of ABCA1 by LPS.

Therefore, this suggests that both transport of LPS from the plasma membrane to an intracellular site and activation of p38 MAP kinase are involved in the LPS-mediated induction of ABCA1.

Abbreviations: ABCA1, ATP-binding cassette transporter 1; LPS, bacterial lipopolysaccharide; MMP-9, matrix metalloproteinase 9; OH Ch, hydroxycholesterol

Supplementary key words LPS • HDL • lipid transporter • regulation • nuclear hormone receptor • CYP7A • MAP kinase

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