Bacterial lipopolysaccharide induces expression of ABCA1 but not ABCG1 via an LXR-independent pathway.
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.
Kaplan
Rebecca
R
Department of Atherosclerosis and Endocrinology, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
Gan
Xiaodong
X
Menke
John G
JG
Wright
Samuel D
SD
Cai
Tian-Quan
TQ
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D000818:Animals; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008070:Lipopolysaccharides / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D008024:Ligands; D008070:Lipopolysaccharides; D002790:Cholesterol 7-alpha-Hydroxylase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases