LXR Driven Induction of HDL‐Cholesterol is Independent of Intestinal Cholesterol Absorption and ABCA1 Protein Expression
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- Kristina Kannisto
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet Karolinska University Hospital Huddinge Stockholm 141 86 Sweden
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- Mats Gåfvels
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet Karolinska University Hospital Huddinge Stockholm 141 86 Sweden
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- Zhao‐Yan Jiang
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet Karolinska University Hospital Huddinge Stockholm 141 86 Sweden
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- Katharina Slätis
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet Karolinska University Hospital Huddinge Stockholm 141 86 Sweden
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- Xiaoli Hu
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet Karolinska University Hospital Huddinge Stockholm 141 86 Sweden
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- Carl Jorns
- Department of Clinical Science, Intervention and Technology (CLINTEC) Karolinska Institutet Huddinge Stockholm 141 86 Sweden
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- Knut R. Steffensen
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet Karolinska University Hospital Huddinge Stockholm 141 86 Sweden
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- Gösta Eggertsen
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet Karolinska University Hospital Huddinge Stockholm 141 86 Sweden
説明
<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>Apoa1</jats:italic> 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.</jats:p>
収録刊行物
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- Lipids
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Lipids 49 (1), 71-83, 2013-10-27
Wiley
