LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling

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Abstract

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-κB 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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Ayaka Ito

Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Cynthia Hong

Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Xin Rong

Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Xuewei Zhu

Department of Internal Medicine-Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, United States

Competing interests
No competing interests declared.
Elizabeth J Tarling

Department of Medicine, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Per Niklas Hedde

Laboratory of Fluorescence Dynamics, Biomedical Engineering Department, Center for Complex Biological Systems, University of California, Irvine, Irvine, United States

Competing interests
No competing interests declared.
Enrico Gratton

Laboratory of Fluorescence Dynamics, Biomedical Engineering Department, Center for Complex Biological Systems, University of California, Irvine, Irvine, United States

Competing interests
No competing interests declared.
John Parks

Department of Internal Medicine-Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, United States

Competing interests
No competing interests declared.
Peter Tontonoz

Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States

For correspondence
ptontonoz@mednet.ucla.edu

Competing interests
Peter Tontonoz, Reviewing editor, eLife.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#99-131 and 2003-166) of the University of California, Los Angeles.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.