LXR signaling couples sterol metabolism to proliferation in the acquired immune response
Open accessAbstract
Cholesterol is essential for membrane synthesis; however, the mechanisms that link cellular lipid metabolism to proliferation are incompletely understood. We demonstrate here that cellular cholesterol levels in dividing T cells are maintained in part through reciprocal regulation of the LXR and SREBP transcriptional programs. T cell activation triggers induction of the oxysterol-metabolizing enzyme SULT2B1, consequent suppression of the LXR pathway for cholesterol transport, and promotion of the SREBP pathway for cholesterol synthesis. Ligation of LXR during T cell activation inhibits mitogen-driven expansion, whereas loss of LXRbeta confers a proliferative advantage. Inactivation of the sterol transporter ABCG1 uncouples LXR signaling from proliferation, directly linking sterol homeostasis to the antiproliferative action of LXR. Mice lacking LXRbeta exhibit lymphoid hyperplasia and enhanced responses to antigenic challenge, indicating that proper regulation of LXR-dependent sterol metabolism is important for immune responses. These results implicate LXR signaling in a metabolic checkpoint that modulates cell proliferation and immunity.
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Limiting intracellular sterol availability by pharmacologically driving the LXR pathway inhibits the proliferation of rapidly dividing cell types such as lymphocytes.
“We previously showed that limiting intracellular sterol availability by pharmacologically driving the LXR pathway inhibits the proliferation of rapidly dividing cell types such as lymphocytes (28).”
From An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway (2011) · cites this paper as [28]
The Results report that LXR agonists block lymphocyte proliferation through ABCG1-dependent changes in intracellular sterol metabolism, and that excess mevalonate reverses the inhibition. The Discussion describes the more specific mechanism of localized sterol depletion as likely, rather than established; the claim presents that limitation of sterol availability as fact. (LLM, conf=0.84)
Experimental — accuracy not yet measuredLXR agonists not only block exogenous LDL uptake, they also actively promote cholesterol removal from cells and intracellular distribution out of the endoplasmic reticulum.
“Such drugs not only block exogenous LDL uptake, they also actively promote cholesterol removal from cells and intracellular distribution out of the endoplasmic reticulum (ER) (28).”
From An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway (2011) · cites this paper as [28]
The Discussion (page not provided) links LXR-induced ABCG1 expression to sterol efflux and describes redistribution of sterols out of the ER, though it presents the effect of LXR agonists on these processes as a likely mechanism rather than a directly measured outcome. The Results section on cholesterol homeostasis (page not provided) says added LDL did not change proliferation; it does not show that LXR agonists block LDL uptake. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThese trends are likely driven by ABCA1 expression extrinsic to T cells (i.e., in MCs), as cholesterol efflux has been shown to impair T cell expansion and activity.
“These trends are likely driven by ABCA1 expression extrinsic to T cells (ie: in MCs), as cholesterol efflux has been shown to impair T cell expansion and activity (39, 40).”
From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [39]
The Results section reports that LXR activation reduces T-cell proliferation through an ABCG1-dependent change in sterol metabolism; it also links LXR signaling to antigen-driven T-cell responses. But the Discussion describes sterol efflux or redistribution as a likely mechanism, not cholesterol efflux as an established cause. The paper does not show that ABCA1 expression outside T cells drives the citing authors’ trends; its experiments instead find that loss of ABCA1 does not alter the T-cell response to LXR agonists. (LLM, conf=0.85)
Experimental — accuracy not yet measuredCholesterol efflux has been shown to impair T cell expansion and activity.
“as cholesterol efflux has been shown to impair T cell expansion and activity (39, 40).”
From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [39]
The Results section, “LXR inhibits proliferation through Abcg1-dependent alteration of cholesterol homeostasis” (page unavailable), shows that LXR activation inhibits T-cell proliferation through ABCG1-dependent sterol transport. The Discussion says the mechanism is likely sterol efflux or intracellular redistribution, rather than establishing cholesterol efflux specifically. The paper also reports effects on antigen-driven responses, but says markers of T-cell activation and IL-2 production were unaffected, so “activity” is too broad if it includes activation. (LLM, conf=0.85)
Experimental — accuracy not yet measuredCholesterol is required to support the rapid clonal expansion of T cells post-activation.
“Cholesterol is required to support the rapid clonal expansion of T cells post-activation (39, 40); plasma membrane cholesterol abundance being required for T-cell receptor clustering and signaling (69).”
From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [39]
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- Authors
- Bensinger, S. J., Bradley, M. N., Joseph, S. B., Zelcer, N., Janssen, E. M., Hausner, M. A., Shih, R., Parks, J. S., Edwards, P. A., Jamieson, B. D., & Tontonoz, P.
- Affiliations
- Howard Hughes Medical Institute (US)
- La Jolla Institute for Immunology (US)
- University of California, Los Angeles (US)
- Wake Forest University Health Sciences (US)
- Corresponding author
- Tontonoz, Peter
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2008-07
- Volume
- 134
- Issue
- 1
- Pages
- 97-111
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2626438
- OpenAlex
- W2104016841
- Cited by
- 711
- References
- 2
- Citations by year
- 2026: 26 · 2025: 31 · 2024: 53 · 2023: 37 · 2022: 35 · 2021: 56 · 2020: 47 · 2019: 46 · 2018: 37 · 2017: 37 · 2016: 38 · 2015: 45 · 2014: 43 · 2013: 37 · 2012: 41
- FWCI
- 35.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL3 0568, P01HL030568, HL049373, R01HL066088, P01HL049373)
- National Cancer Institute (CA-16 042, P30CA016042)
- National Institute of Allergy and Infectious Diseases (AI-28 697, P30AI028697)
- National Center for Research Resources (K01RR021975, RR021975)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Keywords
- LXRβ, SREBP, cholesterol metabolism, T cell proliferation, T cell activation, SULT2B1, ABCG1, sterol transport, lymphoid hyperplasia, adaptive immunity
- MeSH terms
- Liver X Receptors, Aging, Animals, DNA-Binding Proteins, Humans, Lymphocyte Activation, Mice, Inbred C57BL, Sterols, T-Lymphocytes, Signal Transduction, Receptors, Cytoplasmic and Nuclear, Cell Proliferation, Mice, Sterol Regulatory Element Binding Protein 2, Orphan Nuclear Receptors
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