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. 2012 Sep;249(1):72-83.
doi: 10.1111/j.1600-065X.2012.01153.x.

Liver X Receptor and Peroxisome Proliferator-Activated Receptor as Integrators of Lipid Homeostasis and Immunity

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Liver X Receptor and Peroxisome Proliferator-Activated Receptor as Integrators of Lipid Homeostasis and Immunity

Yoko Kidani et al. Immunol Rev. .
Free PMC article


Lipid metabolism has emerged as an important modulator of innate and adaptive immune cell fate and function. The lipid-activated transcription factors peroxisome proliferator-activated receptor (PPAR) α, β/δ, γ and liver X receptor (LXR) are members of the nuclear receptor superfamily that have a well-defined role in regulating lipid homeostasis and metabolic diseases. Accumulated evidence over the last decade indicates that PPAR and LXR signaling also influence multiple facets of inflammation and immunity, thereby providing important crosstalk between metabolism and immune system. Herein, we provide a brief introduction to LXR and PPAR biology and review recent discoveries highlighting the importance of PPAR and LXR signaling in the modulation of normal and pathologic states of immunity. We also examine advances in our mechanistic understanding of how nuclear receptors impact immune system function and homeostasis. Finally, we discuss whether LXRs and PPARs could be pharmacologically manipulated to provide novel therapeutic approaches for modulation of the immune system under pathologic inflammation or in the context of allergic and autoimmune disease.


Figure 1
Figure 1. Mechanism of transcriptional control by LXR and PPAR
(A) Repression: In the unliganded state, LXR/RXR and PPAR/RXR heterodimers are bound to DNA response elements in association with co-repressor complexes resulting in repression of target genes. (B) Activation: Ligand binding to LXR or PPAR induces conformational changes leading to release of co-repressor complexes and recruitment of co-activator complexes and transcription of target genes. (C) Transrepression: Activation of PPAR or LXR represses inflammatory gene expression by maintaining co-repressors on the promoters of NF-κB target genes. In quiescent cells, inflammatory genes are held in a repressed state by co-repressor complexes. Upon TLR signaling, co-repressor complexes are ubiquitinated and subsequently degraded by 19S proteasome in an Ubiquitin-Conjugating Enzyme 5 (UBC5)-dependent manner. TLR signaling also activates NF-κB, resulting in nuclear translocation and binding to inflammatory gene promoters in association with co-activators resulting in target gene expression. Activation of PPARγ or LXR preserves corepressors on the promoters of NF-κB target genes thereby preventing inflammatory gene expression.
Figure 2
Figure 2. LXR and PPARβ/δ drive a program facilitating the clearance of apoptotic cells and maintenance of self-tolerance
LXR and PPARβ/δ play critical roles in coordinating the efficient clearance of apoptotic cells and preserving a tolerogenic program in APCs. Lipids (sterols and fatty acids) from engulfed apoptotic cells activate LXRs and PPARβ/δ in phagocytes resulting in the transactivation of genes involved in receptor-mediated phagocytosis. LXR transactivates the phagocytosis receptor Mertk, whereas PPARβ/δ drives the expression of opsonins (e.g., C1q, MGFE8) coat apoptotic cells to facilitate phagocytosis. Activation of these NRs also results in the transrepression of proinflammatory genes as detailed in the text. Genetic ablation of these NRs results in the accumulation of cellular debris in vivo and the loss of self-tolerance.
Figure 3
Figure 3. The influence of PPAR and LXR on T helper differentiation
LXR and PPAR impacts T helper differentiation through indirect and direct mechanisms. Activation of LXR and PPAR can inhibit inflammatory cytokine expression from APCs thereby influencing T helper cell differentiation. Likewise, activation of NRs can directly influence T helper differentiation through distinct mechanisms (detailed in the text). Activation of PPARγ, PPARβ/δ and LXR negatively influence TH17 differentiation via the regulation of RORγt, AHR, and expression of IL-17. PPARα and PPARβ/δ skew the balance of TH1 and TH2 cells. PPARα and PPARγ agonists have also been shown to activate Foxp3 transcription and the differentiation of Tregs. To date, the importance of these NRs in T follicular cells has not been addressed.

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