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 LXRα (liver X receptor α) and ABCA1 (ATP-binding cassette transporter A1) was also decreased in acLDL-loaded CES1KD macrophages, suggesting reduced signaling through PPARγ–CYP27A1–LXRα. Consistent with this, treatment of CES1KD macrophages with agonists for PPARγ, RAR, and/or RAR/RXR partially restored transcription of CYP27A1 and LXRα, and repaired cholesterol influx. Conversely, treatment of control macrophages with antagonists for PPARγ and/or RXR decreased transcription of CYP27A1 and LXRα. 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 PPARγ 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 PPARγ knockdown cells following acLDL exposures, further suggesting a mechanistic link between CES1 and PPARγ. These results are consistent with a model in which abrogation of CES1 function attenuates the CYP27A1–LXRα–ABCA1 signaling axis by depleting endogenous ligands for the nuclear receptors PPARγ, RAR, and/or RXR that regulate cholesterol homeostasis.
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SR proteins guide the assembly of the macromolecular spliceosome for the splicing of precursor mRNA transcripts. In this issue of Biochemical Journal, Aubol et al. demonstrate that a complex of two protein kinases- SRPK1 and CLK1- can be induced in the nucleus to promote release of the SR protein SRSF1 from storage speckles, a critical step for splicing activation. The image shows the import of SRPK1 from the cytoplasm to the nucleus and the reduction of storage speckles upon the treatment of HeLa cells with the growth factor EGF.
Silencing carboxylesterase 1 in human THP-1 macrophages perturbs genes regulated by PPARγ/RXR and RAR/RXR: down-regulation of CYP27A1–LXRα signaling
Lee C. Mangum, Xiang Hou, Abdolsamad Borazjani, Jung Hwa Lee, Matthew K. Ross, J. Allen Crow; Silencing carboxylesterase 1 in human THP-1 macrophages perturbs genes regulated by PPARγ/RXR and RAR/RXR: down-regulation of CYP27A1–LXRα signaling. Biochem J 14 February 2018; 475 (3): 621–642. doi: https://doi.org/10.1042/BCJ20180008
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