Journal Article

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

Tontonoz, Peter, Tarling, Elizabeth J, Parks, John, Gratton, Enrico, Zhu, Xuewei, Ito, Ayaka, Rong, Xin, Hong, Cynthia, Hedde, Per Niklas

2015

Overview

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. Inflammation is a normal part of the immune response to infection or tissue damage. However, increased inflammation has been linked to diseases such as obesity, diabetes and atherosclerosis (in which the walls of the arteries become hardened). These same diseases have also been linked to problems with the production or breakdown of fatty molecules, such as cholesterol. Transcription factors are proteins that bind to DNA to control gene expression. A transcription factor called LXR regulates the production and breakdown of cholesterol in response to changing levels of cholesterol in the body. LXR has also been shown to inhibit inflammatory responses, but previous studies suggested that these two actions of LXR are independent of each other. Ito et al. have now challenged these findings by showing that LXR inhibits inflammation via changes in the metabolism of cholesterol and other fatty molecules. The experiments used genetically engineered immune cells, called macrophages, and mice to show that activating LXR causes cholesterol molecules to move between the membranes in a cell. This in turn leads to changes in the signals sent by proteins found at the cell surface, and eventually to a reduction of inflammation responses. Future work will focus on better understanding the link between LXR's effects on metabolism and inflammation in models of human diseases such as diabetes and atherosclerosis.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: ABCA1 protein / Animals / ATP Binding Cassette Transporter 1 - metabolism / ATP-binding protein / Bone marrow / Cell Biology / Cell Membrane - chemistry / Cells, Cultured / Cholesterol / Chromatin Immunoprecipitation / Gene expression / Gene Expression Profiling / Genes and Chromosomes / Homeostasis / Inflammation / Laboratories / Ligands / Lipid metabolism / Lipids / Liver X Receptors / LXR / MAP kinase / Medicine / Membrane composition / Metabolism / Mice / MyD88 protein / NF-κB protein / nuclear receptor / Orphan Nuclear Receptors - metabolism / Rodents / Signal Transduction / Software / Sterols / SUMO protein / Toll-like receptor / Toll-Like Receptors - metabolism / TRAF6 protein / Transcription activation