Pharmacological LXR activation reduces presence of SR-B1 in liver membranes contributing to LXR-mediated induction of HDL-cholesterol

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• 作者：Aldo Grefhorst^a ; ¹ ; Maaike H. Oosterveer^a ; Gemma Brufau^a ; Marije Boesjes^a ; Folkert Kuipers^a ; ^b ; Albert K. Groen^a ; ^b ; ^{a.k.groen@med.umcg.nl}
• 关键词：ABC ; ATP binding cassette ; ApoAI ; apolipoprotein AI ; FPLC ; fast protein liquid chromatography ; HDL ; high density lipoprotein ; LXR ; liver X receptor ; SR-B1 ; scavenger receptor-1B ; SREBP-1c ; sterol-regulatory element-binding protein-1c ; TICE ; transintestina
• 刊名：Atherosclerosis
• 出版年：2012
• 期刊代码：28_00219150
• 类别：med
• 出版时间：June, 2012
• 卷：222
• 期：2
• 页码：382-389
• 文件大小：720 K

摘要

class="h4">Objective

Pharmacological LXR activation has anti-atherosclerotic actions in animal models. Part of these beneficial effects may be explained by accelerated reverse cholesterol transport since both plasma high density lipoprotein (HDL) cholesterol and fecal neutral sterol secretion are higher upon LXR activation. Mechanisms underlying these LXR-mediated effects have not been fully elucidated.

class="h4">Methods

We investigated the roles of the isoforms LXR伪 and LXR尾 and the HDL cholesterol uptake receptor SR-B1 in modulation of cholesterol metabolism upon treatment of mice with the LXR ligand T0901317.

class="h4">Results

HDL cholesterol was maximally 60%increased in a time-dependent fashion due to appearance of more and larger HDL particles. Fecal neutral sterol secretion was maximally induced after 1 week treatment. T0901317 treatment induced fecal neutral sterol secretion by 鈭?00%in wild-type but not in Lxr伪 deficient mice. Surprisingly, LXR activation reduced SR-B1 protein amount in hepatic membranes, suggesting that this might contribute to elevated HDL cholesterol. However, T0901317 still elevated plasma HDL cholesterol in Sr-b1 deficient mice, suggesting that SR-B1 is not the only step involved in LXR-mediated induction of plasma HDL cholesterol. In addition, SR-B1 is not essential for LXR-induced cholesterol removal from the body.

class="h4">Conclusion

Induction of fecal neutral sterol secretion by T0901317 critically depends on LXR伪 but not on LXR尾. LXR activation reduces SR-B1 in hepatic membranes, probably partly contributing to elevated HDL cholesterol. SR-B1 is not required to enhance fecal neutral sterol secretion.