Activation of the constitutive androstane receptor decreases HDL in wild-type and human apoA-I transgenic mice.
The nuclear hormone receptor constitutive androstane receptor (CAR, NR1I3) regulates detoxification of xenobiotics and endogenous molecules, and has been shown to be involved in the metabolism of hepatic bile acids and cholesterol. The goal of this study was to address potential effects of CAR on the metabolism of HDL particles, key components in the reverse transport of cholesterol to the liver. Wild-type (WT) mice, transgenic mice expressing human apolipoprotein A-I (HuAITg), and CAR-deficient (CAR(-/-)) mice were treated with the specific CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP). CAR activation decreased HDL cholesterol and plasma apolipoprotein A-I (apoA-I) levels in both WT and HuAITg mice, but not CAR(-/-) mice. Both mouse apoA-I and human apoA-I were decreased by more than 40% after TCPOBOP treatment, and kinetic studies revealed that the production rate of HDL is reduced in TCPOBOP-treated WT mice. In transient transfections, TCPOBOP-activated CAR decreased the activity of the human apoA-I promoter. Although loss of CAR function did not alter HDL levels in normal chow-fed mice, HDL cholesterol, apoA-I concentration, and apoA-I mRNA levels were increased in CAR(-/-) mice relative to WT mice when both were fed a high-fat diet. We conclude that CAR activation in mice induces a pronounced decrease in circulating levels of plasma HDL, at least in part through downregulation of apoA-I gene expression.
Masson
David
D
Institut National de la Santé et de la Recherche Médicale U866, Faculté de Médecine, Dijon Cedex, France.
Qatanani
Mohamed
M
Sberna
Anne Laure
AL
Xiao
Rui
R
Pais de Barros
Jean Paul
JP
Grober
Jacques
J
Deckert
Valerie
V
Athias
Anne
A
Gambert
Philippe
P
Lagrost
Laurent
L
Moore
David D
DD
Assem
Mahfoud
M
D000818:Animals; D016632:Apolipoprotein A-I / Q000502:physiology*; D001483:Base Sequence; D008076:Cholesterol, HDL / Q000378:metabolism; D000090702:Constitutive Androstane Receptor; D004041:Dietary Fats / Q000008:administration & dosage; D015536:Down-Regulation; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood*; D051379:Mice; D008822:Mice, Transgenic; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000502:physiology*; D014157:Transcription Factors / Q000172:deficiency / Q000502:physiology*
D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D000090702:Constitutive Androstane Receptor; D004041:Dietary Fats; D008075:Lipoproteins, HDL; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011725:Pyridines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C489540:Abcc4 protein, mouse; C000716327:NR1I3 protein, human; C000716328:Nr1i3 protein, mouse; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene