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LXR Driven Induction of HDL-Cholesterol is Independent of Intestinal Cholesterol Absorption and ABCA1 Protein Expression

Kannisto, Kristina; Gåfvels, Mats LU ; Jiang, Zhao-Yan; Slatis, Katharina; Hu, Xiaoli; Jorns, Carl; Steffensen, Knut R. and Eggertsen, Gosta (2014) In Lipids 49(1). p.71-83
Abstract
We investigated whether: (1) liver X receptor (LXR)-driven induction of high-density lipoprotein cholesterol (HDL-C) and other LXR-mediated effects on cholesterol metabolism depend on intestinal cholesterol absorption; and (2) combined treatment with the LXR agonist GW3965 and the cholesterol absorption inhibitor ezetimibe results in synergistic effects on cholesterol metabolism that could be beneficial for treatment of atherosclerosis. Mice were fed 0.2 % cholesterol and treated with GW3965+ezetimibe, GW3965 or ezetimibe. GW3965+ezetimibe treatment elevated serum HDL-C and Apolipoprotein (Apo) AI, effectively reduced the intestinal cholesterol absorption and increased the excretion of faecal neutral sterols. No changes in intestinal... (More)
We investigated whether: (1) liver X receptor (LXR)-driven induction of high-density lipoprotein cholesterol (HDL-C) and other LXR-mediated effects on cholesterol metabolism depend on intestinal cholesterol absorption; and (2) combined treatment with the LXR agonist GW3965 and the cholesterol absorption inhibitor ezetimibe results in synergistic effects on cholesterol metabolism that could be beneficial for treatment of atherosclerosis. Mice were fed 0.2 % cholesterol and treated with GW3965+ezetimibe, GW3965 or ezetimibe. GW3965+ezetimibe treatment elevated serum HDL-C and Apolipoprotein (Apo) AI, effectively reduced the intestinal cholesterol absorption and increased the excretion of faecal neutral sterols. No changes in intestinal ATP-binding cassette (ABC) A1 or ABCG5 protein expression were observed, despite increased mRNA expression, while hepatic ABCA1 was slightly reduced. The combined treatment caused a pronounced down-regulation of intestinal Niemann-Pick C1-like 1 (NPC1L1) and reduced hepatic and intestinal cholesterol levels. GW3965 did not affect the intestinal cholesterol absorption, but increased serum HDL-C and ApoAI levels. GW3965 also increased Apoa1 mRNA levels in primary mouse hepatocytes and HEPA1-6 cells. Ezetimibe reduced the intestinal cholesterol absorption, ABCA1 and ABCG5, but did not affect the serum HDL-C or ApoAI levels. Thus, the LXR-driven induction of HDL-C and ApoAI was independent of the intestinal cholesterol absorption and increased expression of intestinal or hepatic ABCA1 was not required. Inhibited influx of cholesterol via NPC1L1 and/or low levels of intracellular cholesterol prevented post-transcriptional expression of intestinal ABCA1 and ABCG5, despite increased mRNA levels. Combined LXR activation and blocked intestinal cholesterol absorption induced effective faecal elimination of cholesterol. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
GW3965, Ezetimibe, Intestinal cholesterol absorption, LXR, HDL, ApoAI, ABCA1, ABCG5, NPC1L1
in
Lipids
volume
49
issue
1
pages
71 - 83
publisher
Springer
external identifiers
  • wos:000329241600007
  • scopus:84891862000
ISSN
0024-4201
DOI
10.1007/s11745-013-3853-8
language
English
LU publication?
yes
id
b1f65edd-60b7-4848-8ccc-ff794c2c5b95 (old id 4255892)
date added to LUP
2014-02-10 12:13:21
date last changed
2017-09-24 03:07:52
@article{b1f65edd-60b7-4848-8ccc-ff794c2c5b95,
  abstract     = {We investigated whether: (1) liver X receptor (LXR)-driven induction of high-density lipoprotein cholesterol (HDL-C) and other LXR-mediated effects on cholesterol metabolism depend on intestinal cholesterol absorption; and (2) combined treatment with the LXR agonist GW3965 and the cholesterol absorption inhibitor ezetimibe results in synergistic effects on cholesterol metabolism that could be beneficial for treatment of atherosclerosis. Mice were fed 0.2 % cholesterol and treated with GW3965+ezetimibe, GW3965 or ezetimibe. GW3965+ezetimibe treatment elevated serum HDL-C and Apolipoprotein (Apo) AI, effectively reduced the intestinal cholesterol absorption and increased the excretion of faecal neutral sterols. No changes in intestinal ATP-binding cassette (ABC) A1 or ABCG5 protein expression were observed, despite increased mRNA expression, while hepatic ABCA1 was slightly reduced. The combined treatment caused a pronounced down-regulation of intestinal Niemann-Pick C1-like 1 (NPC1L1) and reduced hepatic and intestinal cholesterol levels. GW3965 did not affect the intestinal cholesterol absorption, but increased serum HDL-C and ApoAI levels. GW3965 also increased Apoa1 mRNA levels in primary mouse hepatocytes and HEPA1-6 cells. Ezetimibe reduced the intestinal cholesterol absorption, ABCA1 and ABCG5, but did not affect the serum HDL-C or ApoAI levels. Thus, the LXR-driven induction of HDL-C and ApoAI was independent of the intestinal cholesterol absorption and increased expression of intestinal or hepatic ABCA1 was not required. Inhibited influx of cholesterol via NPC1L1 and/or low levels of intracellular cholesterol prevented post-transcriptional expression of intestinal ABCA1 and ABCG5, despite increased mRNA levels. Combined LXR activation and blocked intestinal cholesterol absorption induced effective faecal elimination of cholesterol.},
  author       = {Kannisto, Kristina and Gåfvels, Mats and Jiang, Zhao-Yan and Slatis, Katharina and Hu, Xiaoli and Jorns, Carl and Steffensen, Knut R. and Eggertsen, Gosta},
  issn         = {0024-4201},
  keyword      = {GW3965,Ezetimibe,Intestinal cholesterol absorption,LXR,HDL,ApoAI,ABCA1,ABCG5,NPC1L1},
  language     = {eng},
  number       = {1},
  pages        = {71--83},
  publisher    = {Springer},
  series       = {Lipids},
  title        = {LXR Driven Induction of HDL-Cholesterol is Independent of Intestinal Cholesterol Absorption and ABCA1 Protein Expression},
  url          = {http://dx.doi.org/10.1007/s11745-013-3853-8},
  volume       = {49},
  year         = {2014},
}