| First Author | Hong C | Year | 2012 |
| Journal | J Lipid Res | Volume | 53 |
| Issue | 6 | Pages | 1126-33 |
| PubMed ID | 22454476 | Mgi Jnum | J:184910 |
| Mgi Id | MGI:5426729 | Doi | 10.1194/jlr.M022061 |
| Citation | Hong C, et al. (2012) LXRalpha is uniquely required for maximal reverse cholesterol transport and atheroprotection in ApoE-deficient mice. J Lipid Res 53(6):1126-33 |
| abstractText | The liver X receptor (LXR) signaling pathway is an important modulator of atherosclerosis, but the relative importance of the two LXRs in atheroprotection is incompletely understood. We show here that LXRalpha, the dominant LXR isotype expressed in liver, plays a particularly important role in whole-body sterol homeostasis. In the context of the ApoE(-/-) background, deletion of LXRalpha, but not LXRbeta, led to prominent increases in atherosclerosis and peripheral cholesterol accumulation. However, combined loss of LXRalpha and LXRbeta on the ApoE(-/-) background led to an even more severe cholesterol accumulation phenotype compared to LXRalpha(-/-)ApoE(-/-) mice, indicating that LXRbeta does contribute to reverse cholesterol transport (RCT) but that this contribution is quantitatively less important than that of LXRalpha. Unexpectedly, macrophages did not appear to underlie the differential phenotype of LXRalpha(-/-)ApoE(-/-) and LXRbeta(-/-)ApoE(-/-) mice, as in vitro assays revealed no difference in the efficiency of cholesterol efflux from isolated macrophages. By contrast, in vivo assays of RCT using exogenously labeled macrophages revealed a marked defect in fecal sterol efflux in LXRalpha(-/-)ApoE(-/-) mice. Mechanistically, this defect was linked to a specific requirement for LXRalpha(-/-) in the expression of hepatic LXR target genes involved in sterol transport and metabolism. These studies reveal a previously unrecognized requirement for hepatic LXRalpha for optimal reverse cholesterol transport in mice. |
