• Register
X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

X

Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.

No
Yes

Liver LXRα expression is crucial for whole body cholesterol homeostasis and reverse cholesterol transport in mice.

Liver X receptors (LXRα and LXRβ) 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 LXRα in hepatocytes. Liver-specific deletion of LXRα in mice substantially decreased reverse cholesterol transport, cholesterol catabolism, and cholesterol excretion, revealing the essential importance of hepatic LXRα for whole body cholesterol homeostasis. Additionally, in a pro-atherogenic background, liver-specific deletion of LXRα 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 LXRα, 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 LXRα 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.

Pubmed ID: 22484817

Authors

  • Zhang Y
  • Breevoort SR
  • Angdisen J
  • Fu M
  • Schmidt DR
  • Holmstrom SR
  • Kliewer SA
  • Mangelsdorf DJ
  • Schulman IG

Journal

The Journal of clinical investigation

Publication Data

May 1, 2012

Associated Grants

  • Agency: NHLBI NIH HHS, Id: 1R01HL096864-01A1
  • Agency: NIGMS NIH HHS, Id: T32 GM007055
  • Agency: NIDDK NIH HHS, Id: U19DK62434
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Anticholesteremic Agents
  • Atherosclerosis
  • Bile Acids and Salts
  • Biological Transport
  • Cells, Cultured
  • Cholesterol
  • Feces
  • Female
  • Gene Knockout Techniques
  • Homeostasis
  • Hydrocarbons, Fluorinated
  • Lipid Metabolism
  • Lipoproteins
  • Liver
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Organ Specificity
  • Orphan Nuclear Receptors
  • Particle Size
  • Sulfonamides
  • Triglycerides