Differential Regulation of Gene Expression by LXRs in Response to Macrophage Cholesterol Loading

Abstract

The ability of cells to precisely control gene expression in response to intracellular and extracellular signals plays an important role in both normal physiology and in pathological settings. For instance, the accumulation of excess cholesterol by macrophages initiates a genetic response mediated by the liver X receptors (LXRs)-α (NR1H3) and LXRβ (NR1H2), which facilitates the transport of cholesterol out of cells to high-density lipoprotein particles. Studies using synthetic LXR agonists have also demonstrated that macrophage LXR activation simultaneously induces a second network of genes that promotes fatty acid and triglyceride synthesis that may support the detoxification of excess free cholesterol by storage in the ester form. We now show that treatment of human THP-1 macrophages with endogenous or synthetic LXR ligands stimulates both transcriptional and posttranscriptional pathways that result in the selective recruitment of the LXRα subtype to LXR-regulated promoters. Interestingly, when human or mouse macrophages are loaded with cholesterol under conditions that mimic the development of atherogenic macrophage foam cells, a selective LXR response is generated that induces genes mediating cholesterol transport but does not coordinately regulate genes involved in fatty acid synthesis. The gene-selective response to cholesterol loading occurs, even in the presence of LXRα binding to the promoter of the gene encoding the sterol regulatory element-binding protein-1c, the master transcriptional regulator of fatty acid synthesis. The ability of promoter bound LXRα to recruit RNA polymerase to the sterol regulatory element-binding protein-1c promoter, however, appears to be ligand selective.

Alu repeats as transcriptional regulatory platforms in macrophage responses toM. tuberculosisinfection

“…These results suggest that infection under these conditions is not accompanied by an increased production of endogenous LXR agonists. Indeed, we did not observe any substantial regulation of genes encoding the enzymes CYP27A1, CYP46A1, CH25H and DHCR24 (Supplementary Figure S4B), which catalyze the formation of endogenous LXR ligands (38,39), a result confirmed by RT-qPCR (Supplementary Figure S4C). While the catalytic activities or expression levels of these enzymes could be regulated post-transcriptionally, the data taken together indicate that the enhanced expression of LXRα in infected cells is not accompanied by an increase in the proportion of agonist-bound receptor under these conditions.…”

The influence of ligand-activated LXR on primary human trophoblasts

“…Our findings are consistent with those of Ignatova, et al ., who demonstrated that acetylated LDL promoted recruitment of LXRα to LXR response elements (LXREs) in the promoters of both ABCA1 and SREBP-1c, but led to transcription and RNA polymerase II recruitment for ABCA1 only [15]. In addition to binding of LXREs, the extent to which LXR ligands promote transcription of specific gene targets is also determined by the complement of additional activators recruited to specific promoters [13], the differential displacement of corepressors such as NCoR [38], and the stability of conformational changes induced by ligand binding [39].…”

“…In addition to tissue-specific variation, the effect of LXR activation is also ligand dependent. While synthetic LXR ligands promote expression of both ABCA1 and SREBP1-c in cultured human macrophages and 293T cells, endogenous ligands lead to increased expression of ABCA1 only, with no effect on expression of SREBP1-c [15]. …”

4β-hydroxycholesterol is a pro-lipogenic factor that promotes SREBP1c expression and activity through Liver X-receptor

“…3B). Interestingly, we noticed that 4b-HC treatment increased LXRa protein levels, a stabilizing effect observed for other established LXR ligands (Ignatova et al, 2013) (Fig. 3C).…”