| First Author | Zhang Y | Year | 2012 |
| Journal | J Clin Invest | Volume | 122 |
| Issue | 5 | Pages | 1688-99 |
| PubMed ID | 22484817 | Mgi Jnum | J:184536 |
| Mgi Id | MGI:5424292 | Doi | 10.1172/JCI59817 |
| Citation | Zhang Y, et al. (2012) Liver LXRalpha expression is crucial for whole body cholesterol homeostasis and reverse cholesterol transport in mice. J Clin Invest 122(5):1688-99 |
| abstractText | Liver X receptors (LXRalpha and LXRbeta) are important regulators of cholesterol and lipid metabolism, and their activation has been shown to inhibit cardiovascular disease and reduce atherosclerosis in animal models. Small molecule agonists of LXR activity are therefore of great therapeutic interest. However, the finding that such agonists also promote hepatic lipogenesis has led to the idea that hepatic LXR activity is undesirable from a therapeutic perspective. To investigate whether this might be true, we performed gene targeting to selectively delete LXRalpha in hepatocytes. Liver-specific deletion of LXRalpha in mice substantially decreased reverse cholesterol transport, cholesterol catabolism, and cholesterol excretion, revealing the essential importance of hepatic LXRalpha for whole body cholesterol homeostasis. Additionally, in a pro-atherogenic background, liver-specific deletion of LXRalpha increased atherosclerosis, uncovering an important function for hepatic LXR activity in limiting cardiovascular disease. Nevertheless, synthetic LXR agonists still elicited anti-atherogenic activity in the absence of hepatic LXRalpha, indicating that the ability of agonists to reduce cardiovascular disease did not require an increase in cholesterol excretion. Furthermore, when non-atherogenic mice were treated with synthetic LXR agonists, liver-specific deletion of LXRalpha eliminated the detrimental effect of increased plasma triglycerides, while the beneficial effect of increased plasma HDL was unaltered. In sum, these observations suggest that therapeutic strategies that bypass the liver or limit the activation of hepatic LXRs should still be beneficial for the treatment of cardiovascular disease. |
