ABCA1 p.Leu439Ala
| Predicted by SNAP2: | A: D (63%), C: D (59%), D: D (80%), E: D (71%), F: N (53%), G: D (75%), H: D (71%), I: N (66%), K: D (80%), M: N (78%), N: D (75%), P: D (80%), Q: D (66%), R: D (85%), S: D (53%), T: N (57%), V: N (57%), W: D (75%), Y: D (71%), |
| Predicted by PROVEAN: | A: N, C: N, D: D, E: D, F: N, G: D, H: D, I: N, K: N, M: N, N: N, P: D, Q: N, R: N, S: N, T: N, V: N, W: D, Y: N, |
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[hide] LXRs link metabolism to inflammation through Abca1... Elife. 2015 Jul 14;4:e08009. doi: 10.7554/eLife.08009. Ito A, Hong C, Rong X, Zhu X, Tarling EJ, Hedde PN, Gratton E, Parks J, Tontonoz P
LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling.
Elife. 2015 Jul 14;4:e08009. doi: 10.7554/eLife.08009., [PMID:26173179]
Abstract [show]
The liver X receptors (LXRs) are transcriptional regulators of lipid homeostasis that also have potent anti-inflammatory effects. The molecular basis for their anti-inflammatory effects is incompletely understood, but has been proposed to involve the indirect tethering of LXRs to inflammatory gene promoters. Here we demonstrate that the ability of LXRs to repress inflammatory gene expression in cells and mice derives primarily from their ability to regulate lipid metabolism through transcriptional activation and can occur in the absence of SUMOylation. Moreover, we identify the putative lipid transporter Abca1 as a critical mediator of LXR's anti-inflammatory effects. Activation of LXR inhibits signaling from TLRs 2, 4 and 9 to their downstream NF-kappaB and MAPK effectors through Abca1-dependent changes in membrane lipid organization that disrupt the recruitment of MyD88 and TRAF6. These data suggest that a common mechanism-direct transcriptional activation-underlies the dual biological functions of LXRs in metabolism and inflammation.
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No. Sentence Comment
46 (C) Immortalized MEFs from Lxrb1;-/-Lxrb2; -/- mice reconstituted with wild-type human LXRb1;, L439A/E441A mutant or control mock were pretreated with the LXR agonist GW3965 (1 bc;M) overnight, followed by stimulation with LPS (10 ng/ml) for 4 hr. Gene expression was analyzed by real-time PCR.
X
ABCA1 p.Leu439Ala 26173179:46:104
status: NEW54 Furthermore, an LXR mutant defective in its ability to recruit co-activators, L439A/E441A (Tzukerman et al., 1994; Bastie et al., 2000), was unable to induce Abca1 or to repress inflammatory genes in both MEFs and iBMDM (Figure 1C, Figure 2B, Figure 2-figure supplement 1A), strongly suggesting that gene activation and inflammatory repression are mechanistically linked.
X
ABCA1 p.Leu439Ala 26173179:54:78
status: NEW80 (B, C) Immortalized bone marrow-derived macrophages from Lxrb1;-/-Lxrb2;-/- mice reconstituted with wild-type human LXRb1;, K328R/K434R (KK) mutant, L439A/E441A mutant, or mock control were pretreated with GW3965 (1 bc;M) overnight, followed by stimulation with LPS (10 ng/ml) for 4 hr. Gene expression was analyzed by real-time PCR (B) and Agilent microarrays (C).
X
ABCA1 p.Leu439Ala 26173179:80:158
status: NEW184 We found that an LXR L439A/E441A mutant that lacks co-activator recruitment capacity was unable to repress inflammation.
X
ABCA1 p.Leu439Ala 26173179:184:21
status: NEW