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 language | English (US) |
|---|---|
| Pages (from-to) | 448-454 |
| Number of pages | 7 |
| Journal | Arteriosclerosis, Thrombosis, and Vascular Biology |
| Volume | 28 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 1 2008 |
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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 journal › Article
}
TY - JOUR
T1 - Niemann-pick C1-like 1 is required for an LXR agonist to raise plasma HDL cholesterol in mice
AU - Tang, Weiqing
AU - Ma, Yinyan
AU - Jia, Lin
AU - Ioannou, Yiannis A.
AU - Davies, Joanna P.
AU - Yu, Liqing
PY - 2008/3/1
Y1 - 2008/3/1
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.
AB - 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.
KW - ABCA1
KW - Cholesterol absorption
KW - HDL
KW - Liver x receptor
KW - Niemann-pick C1-like 1
UR - http://www.scopus.com/inward/record.url?scp=40749126815&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=40749126815&partnerID=8YFLogxK
U2 - 10.1161/ATVBAHA.107.160465
DO - 10.1161/ATVBAHA.107.160465
M3 - Article
C2 - 18187667
AN - SCOPUS:40749126815
VL - 28
SP - 448
EP - 454
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
SN - 1079-5642
IS - 3
ER -