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Silencing carboxylesterase 1 in human THP-1 macrophages perturbs genes regulated by PPAR gamma/RXR and RAR/RXR:down-regulation of CYP27A1-LXR alpha signaling

文献类型： 外文期刊

作者： Mangum, Lee C. 1 ; Hou, Xiang 1 ; Borazjani, Abdolsamad 1 ; Lee, Jung Hwa 1 ; Ross, Matthew K. 1 ; Crow, J. Allen 1 ;

作者机构： 1.Mississippi State Univ, Coll Vet Med, Dept Basic Sci, Ctr Environm Hlth Sci, POB 6100, Mississippi State, MS 39762 USA

2.Jiangsu Acad Agr Sci, Inst Food Safety, Nanjing, Jiangsu, Peoples R China

期刊名称：BIOCHEMICAL JOURNAL （ 影响因子：3.857； 五年影响因子：4.868 ）

ISSN： 0264-6021

年卷期： 2018 年 475 卷

页码：

收录情况： SCI

摘要： Macrophage foam cells store excess cholesterol as cholesteryl esters, which need to be hydrolyzed for cholesterol efflux. We recently reported that silencing expression of carboxylesterase 1 (CES1) in human THP-1 macrophages [CES1KD (THP-1 cells with CES1 expression knocked down) macrophages] reduced cholesterol uptake and decreased expression of CD36 and scavenger receptor-A in cells loaded with acetylated low-density lipoprotein (acLDL). Here, we report that CES1KD macrophages exhibit reduced transcription of cytochrome P45027A1 (CYP27A1) in nonloaded and acLDL-loaded cells. Moreover, levels of CYP27A1 protein and its enzymatic product, 27-hydroxycholesterol, were markedly reduced in CES1KD macrophages. Transcription of LXR alpha (liver X receptor alpha) and ABCA1 (ATP-binding cassette transporter A1) was also decreased in acLDL-loaded CES1KD macrophages, suggesting reduced signaling through PPAR gamma-CYP27A1-LXR alpha. Consistent with this, treatment of CES1KD macrophages with agonists for PPAR gamma, RAR, and/or RAR/RXR partially restored transcription of CYP27A1 and LXR alpha, and repaired cholesterol influx. Conversely, treatment of control macrophages with antagonists for PPAR gamma and/or RXR decreased transcription of CYP27A1 and LXR alpha. Pharmacologic inhibition of CES1 in both wild-type THP-1 cells and primary human macrophages also decreased CYP27A1 transcription. CES1 silencing did not affect transcript levels of PPAR gamma and RXR in acLDL-loaded macrophages, whereas it did reduce the catabolism of the endocannabinoid 2-arachidonoylglycerol. Finally, the gene expression profile of CES1KD macrophages was similar to that of PPAR gamma knockdown cells following acLDL exposures, further suggesting a mechanistic link between CES1 and PPAR gamma. These results are consistent with a model in which abrogation of CES1 function attenuates the CYP27A1-LXR alpha-ABCA1 signaling axis by depleting endogenous ligands for the nuclear receptors PPAR gamma, RAR, and/or RXR that regulate cholesterol homeostasis.

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