Liver X receptors (LXRs) regulate apolipoprotein AIV-implications of the antiatherosclerotic effect of LXR agonists.
Liver X receptors (LXRs) regulate target genes that are critical in lipoprotein metabolism and atherosclerosis. Apolipoprotein AIV (ApoAIV) is an apolipoprotein that is associated with chylomicrons and high-density lipoproteins. Plasma ApoAIV level in humans is inversely correlated with coronary artery events and overexpression of ApoAIV in mice results in significant reduction in atherosclerosis. We report here that LXRs directly regulate apoAIV at the transcriptional level. Treatment of C57B6 mice with a synthetic LXR agonist, T0901317, resulted in significant increases in plasma apoAIV that was associated with high-density lipoprotein. Examination of both intestinal and liver apoAIV mRNA revealed specific increases in liver mRNA only. In a human heptoma HepG2 cell model, apoAIV mRNA was up-regulated upon the treatment with either native or synthetic LXR agonists. Nuclear run-on study revealed a significant increase in the ApoAIV transcriptional rate upon LXR activation. Examination of the human apoAIV proximal promoter revealed a potential LXR response element that demonstrated binding with HepG2 nuclear extracts. Cotransfection studies in HepG2 cells indicated that this responsive element was functional in mediating the human ApoAIV gene response to LXR agonists. In addition, we identified a functional LXR-responsive element at 3' end enhancer region of mouse ApoAIV gene. We conclude that ApoAIV is a direct target gene of LXRs that may contribute to the antiatherogenic effect of LXR activation.
Liang
Yu
Y
Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana 46285, USA.
Jiang
Xian-Cheng
XC
Liu
Ruijie
R
Liang
Guosheng
G
Beyer
Thomas P
TP
Gao
Hong
H
Ryan
Timothy P
TP
Dan Li
Shuyu
S
Eacho
Patrick I
PI
Cao
Guoqing
G
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001054:Apolipoproteins A / Q000097:blood / Q000235:genetics*; D001161:Arteriosclerosis / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D008024:Ligands; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D047488:Retinoid X Receptors / Q000378:metabolism; D016415:Sequence Alignment; D013449:Sulfonamides; D014158:Transcription, Genetic / Q000235:genetics; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000924:Anticholesteremic Agents; D001054:Apolipoproteins A; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D047488:Retinoid X Receptors; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C022205:apolipoprotein A-IV