Phospholipid transfer protein is regulated by liver X receptors in vivo.
Liver X receptors (LXR) belong to the nuclear receptor superfamily that can regulate important lipid metabolic pathways. The plasma phospholipid transfer protein (PLTP) is known to mediate transfer of phospholipids from triglyceride-rich lipoproteins to high density lipoprotein (HDL) and plays a critical role in HDL metabolism. We report here that a specific LXR agonist, T0901317, elevated HDL cholesterol and phospholipid in C57/BL6 mice and generated enlarged HDL particles that were enriched in cholesterol, ApoAI, ApoE, and phospholipid. The appearance of these HDL particles upon oral dosing of T0901317 in C57/BL6 mice was closely correlated with the increased plasma PLTP activity and liver PLTP mRNA levels. Nuclear run-on assay indicated that the effect of LXR agonist on PLTP expression was at the transcriptional level. In mouse peritoneal macrophage cells, PLTP expression was also up-regulated by the LXR/RXR (retinoid X receptor) heterodimer. However, cholesterol efflux in mouse peritoneal macrophage cells from PLTP-deficient mice (PLTP0) was not significantly different from wild type animals. Although in PLTP-deficient mice, the induction of HDL cholesterol as well as HDL particle size increase persisted, the extent of the induction was greatly attenuated. We conclude that PLTP is a direct target gene of LXRs in vivo and plays an important role in LXR agonist-mediated HDL cholesterol and size increase in mice.
Cao
Guoqing
G
Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana 46285, USA.
Beyer
Thomas P
TP
Yang
Xiao Ping
XP
Schmidt
Robert J
RJ
Zhang
Youyan
Y
Bensch
William R
WR
Kauffman
Raymond F
RF
Gao
Hong
H
Ryan
Timothy P
TP
Liang
Yu
Y
Eacho
Patrick I
PI
Jiang
Xian-Cheng
XC
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002352:Carrier Proteins / Q000097:blood / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D008076:Cholesterol, HDL / Q000378:metabolism; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006845:Hydrocarbons, Fluorinated; D008024:Ligands; D050356:Lipid Metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism; D008565:Membrane Proteins / Q000097:blood / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors; D049294:Phospholipid Transfer Proteins; D010743:Phospholipids / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000819:agonists / Q000378:metabolism*; D013449:Sulfonamides; D013997:Time Factors; D014158:Transcription, Genetic; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000924:Anticholesteremic Agents; D002352:Carrier Proteins; D002784:Cholesterol; D008076:Cholesterol, HDL; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D008024:Ligands; D008075:Lipoproteins, HDL; D000071518:Liver X Receptors; D008565:Membrane Proteins; D057093:Orphan Nuclear Receptors; D049294:Phospholipid Transfer Proteins; D010743:Phospholipids; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides