LXR Signaling Couples Sterol Metabolism to Proliferation in the Acquired Immune Response

Abstract

Summary We demonstrate here that LXR–dependent sterol homeostasis is a physiologically-regulated determinant of cell proliferation and acquired immune responses. T cell activation triggers simultaneous suppression of the LXR pathway for cholesterol transport and induction of the SREBP pathway for cholesterol synthesis. This coordinated program is engaged in part through induction of the sterol-metabolizing enzyme SULT2B1, expression of which in T cells blocks LXR signaling. Forced induction of LXR target genes during T cell activation markedly inhibits mitogen-driven expansion, whereas loss of LXRβ confers a proliferative advantage. Inactivation of the sterol transporter ABCG1 in T cells uncouples LXR signaling from proliferation, directly linking sterol homeostasis to the anti-proliferative action of LXR. Mice lacking LXRβ exhibit lymphoid hyperplasia and enhanced responses to antigenic challenge, indicating that proper regulation of LXR-dependent sterol metabolism is important for immune responses. These data implicate LXR signaling in a metabolic checkpoint that modulates cell proliferation and immunity.

Nuclear Receptor NR1H3 in Familial Multiple Sclerosis

“…LXRs regulate inflammation by inhibiting the expression of inflammatory mediators including interleukin-6, nitric oxide synthase and cyclooxygenase 2 (Bensinger et al, 2008;Joseph et al, 2003). Mechanistically, the antiinflammatory effects of LXRs have been attributed to the inhibition of nuclear factor kappa-B and STAT1-mediated signaling pathways via transrepression (Glass and Saijo, 2010;Li et al, 2011).…”

ATP-Binding Cassette Proteins Involved in Glucose and Lipid Homeostasis

“…Recent study indicates that ABCG1 also plays a key role in the downregulation of T-cell proliferation and activation. 64) Endogenous ABCG1 is reported to localize to the perinuclear region and, in some cases, to be distributed in the plasma membrane of macrophagederived foam cells. 60,65) It has been reported that ABCG1 mediates the efflux of cholesterol from cells to HDL-2 or HDL-3, but not to lipid-poor apolipoprotein A-I (apoA-I), 49) and that ABCG1 redistributes cholesterol to cell-surface domains accessible for removal by HDL.…”

Inhibition of Advanced Prostate Cancer by Androgens and Liver X Receptor Agonists

“…LXR-ABCG1 signaling was reported to regulate sterol metabolism (Bensinger et al 2008). Activation of LXR inhibited the proliferation of T-cells but had no effect on cell viability (Bensinger et al 2008). Since T0901317 did not inhibit the proliferation of CAOV3 ovarian cancer cells treated with siRNA against LXR or LXR (Scoles et al 2010), it is possible that 22(R)-hydroxycholesterol inhibited cell proliferation mainly through activation of LXR, while inhibition of T0901317 may be caused by both LXR and LXR activation.…”

“…The effective concentrations for 22(R)-hydroxycholesterol to suppress cancer cell growth is within its known physiological range and is much lower than the concentrations to activate other nuclear receptors (Janowski et al 1996). LXR-ABCG1 signaling was reported to regulate sterol metabolism (Bensinger et al 2008). Activation of LXR inhibited the proliferation of T-cells but had no effect on cell viability (Bensinger et al 2008).…”