Niemann-pick C1-like 1 is required for an LXR agonist to raise plasma HDL cholesterol in mice

Weiqing Tang, Yinyan Ma, Lin Jia, Yiannis A. Ioannou, Joanna P. Davies, Liqing Yu

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Objectives: Activation of liver x receptor (LXR) raises plasma HDL-cholesterol (HDL-C) in mice. Interestingly, the LXR agonist GW3965 fails to raise plasma HDL-C in mice lacking intestinal ABCA1, indicating that intestinal ABCA1 plays a predominant role in GW3965-mediated HDL production. How this is coupled to intestinal function remains elusive. Because cholesterol is essential for HDL assembly and directly regulates intestinal ABCA1 expression via activating LXR, we hypothesized that cholesterol absorption, a major function of intestine, modulates LXR-dependent HDL formation. Methods and Results :Mice lacking Niemann-Pick C1-Like 1 (NPC1L1) (L1-KO mice), a gene that is essential for cholesterol absorption, were treated with LXR agonist T0901317 for 7 days. Intriguingly, this treatment failed to significantly raise plasma HDL-C but caused a much greater fecal cholesterol excretion in L1-KO mice. The intestinal ABCA1 mRNA level was about 4-fold lower in L1-KO versus wild-type mice, and increased 3.9-fold and 8.8-fold after T0901317 treatment in wild-type and L1-KO mice, respectively. Hepatic ABCA1 failed to respond to T0901317 in mice of both genotypes, although hepatic mRNAs for many LXR target genes were higher in the T0901317-treated versus untreated wild-type animals. Conclusions: NPC1L1 is required for an LXR agonist to increase plasma HDL-C in mice.

Original languageEnglish (US)
Pages (from-to)448-454
Number of pages7
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume28
Issue number3
DOIs
StatePublished - Mar 1 2008

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HDL Cholesterol
Liver
Cholesterol
Messenger RNA
Wild Animals
Essential Genes
Intestines
Genotype
TO-901317
Genes

Keywords

  • ABCA1
  • Cholesterol absorption
  • HDL
  • Liver x receptor
  • Niemann-pick C1-like 1

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Niemann-pick C1-like 1 is required for an LXR agonist to raise plasma HDL cholesterol in mice. / Tang, Weiqing; Ma, Yinyan; Jia, Lin; Ioannou, Yiannis A.; Davies, Joanna P.; Yu, Liqing.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 28, No. 3, 01.03.2008, p. 448-454.

Research output: Contribution to journalArticle

Tang, Weiqing ; Ma, Yinyan ; Jia, Lin ; Ioannou, Yiannis A. ; Davies, Joanna P. ; Yu, Liqing. / Niemann-pick C1-like 1 is required for an LXR agonist to raise plasma HDL cholesterol in mice. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2008 ; Vol. 28, No. 3. pp. 448-454.
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abstract = "Objectives: Activation of liver x receptor (LXR) raises plasma HDL-cholesterol (HDL-C) in mice. Interestingly, the LXR agonist GW3965 fails to raise plasma HDL-C in mice lacking intestinal ABCA1, indicating that intestinal ABCA1 plays a predominant role in GW3965-mediated HDL production. How this is coupled to intestinal function remains elusive. Because cholesterol is essential for HDL assembly and directly regulates intestinal ABCA1 expression via activating LXR, we hypothesized that cholesterol absorption, a major function of intestine, modulates LXR-dependent HDL formation. Methods and Results :Mice lacking Niemann-Pick C1-Like 1 (NPC1L1) (L1-KO mice), a gene that is essential for cholesterol absorption, were treated with LXR agonist T0901317 for 7 days. Intriguingly, this treatment failed to significantly raise plasma HDL-C but caused a much greater fecal cholesterol excretion in L1-KO mice. The intestinal ABCA1 mRNA level was about 4-fold lower in L1-KO versus wild-type mice, and increased 3.9-fold and 8.8-fold after T0901317 treatment in wild-type and L1-KO mice, respectively. Hepatic ABCA1 failed to respond to T0901317 in mice of both genotypes, although hepatic mRNAs for many LXR target genes were higher in the T0901317-treated versus untreated wild-type animals. Conclusions: NPC1L1 is required for an LXR agonist to increase plasma HDL-C in mice.",
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AU - Davies, Joanna P.

AU - Yu, Liqing

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N2 - Objectives: Activation of liver x receptor (LXR) raises plasma HDL-cholesterol (HDL-C) in mice. Interestingly, the LXR agonist GW3965 fails to raise plasma HDL-C in mice lacking intestinal ABCA1, indicating that intestinal ABCA1 plays a predominant role in GW3965-mediated HDL production. How this is coupled to intestinal function remains elusive. Because cholesterol is essential for HDL assembly and directly regulates intestinal ABCA1 expression via activating LXR, we hypothesized that cholesterol absorption, a major function of intestine, modulates LXR-dependent HDL formation. Methods and Results :Mice lacking Niemann-Pick C1-Like 1 (NPC1L1) (L1-KO mice), a gene that is essential for cholesterol absorption, were treated with LXR agonist T0901317 for 7 days. Intriguingly, this treatment failed to significantly raise plasma HDL-C but caused a much greater fecal cholesterol excretion in L1-KO mice. The intestinal ABCA1 mRNA level was about 4-fold lower in L1-KO versus wild-type mice, and increased 3.9-fold and 8.8-fold after T0901317 treatment in wild-type and L1-KO mice, respectively. Hepatic ABCA1 failed to respond to T0901317 in mice of both genotypes, although hepatic mRNAs for many LXR target genes were higher in the T0901317-treated versus untreated wild-type animals. Conclusions: NPC1L1 is required for an LXR agonist to increase plasma HDL-C in mice.

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