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Liver X receptors in lipid signalling and membrane homeostasis

Nature Reviews Endocrinology volume 14, pages 452–463 (2018)Cite this article

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Abstract

Liver X receptors α and β (LXRα and LXRβ) are nuclear receptors with pivotal roles in the transcriptional control of lipid metabolism. Transcriptional activity of LXRs is induced in response to elevated cellular levels of cholesterol. LXRs bind to and regulate the expression of genes that encode proteins involved in cholesterol absorption, transport, efflux, excretion and conversion to bile acids. The coordinated, tissue-specific actions of the LXR pathway maintain systemic cholesterol homeostasis and regulate immune and inflammatory responses. LXRs also regulate fatty acid metabolism by controlling the lipogenic transcription factor sterol regulatory element-binding protein 1c and regulate genes that encode proteins involved in fatty acid elongation and desaturation. LXRs exert important effects on the metabolism of phospholipids, which, along with cholesterol, are major constituents of cellular membranes. LXR activation preferentially drives the incorporation of polyunsaturated fatty acids into phospholipids by inducing transcription of the remodelling enzyme lysophosphatidylcholine acyltransferase 3. The ability of the LXR pathway to couple cellular sterol levels with the saturation of fatty acids in membrane phospholipids has implications for several physiological processes, including lipoprotein production, dietary lipid absorption and intestinal stem cell proliferation. Understanding how LXRs regulate membrane composition and function might provide new therapeutic insight into diseases associated with dysregulated lipid metabolism, including atherosclerosis, diabetes mellitus and cancer.

Key points

  • Liver X receptors (LXRs) are ligand-activated nuclear receptors that modulate lipid homeostasis.

  • Cellular and systemic cholesterol homeostasis is maintained by LXRs through the regulation of cholesterol absorption, cellular uptake, excretion, reverse transport and biosynthesis in multiple tissues and cell types.

  • LXR activation increases lipogenesis through the control of sterol regulatory element-binding protein 1c and its target genes in liver.

  • LXRs modulate membrane phospholipid composition through inducing the expression of lysophosphatidylcholine acyltransferase 3, an enzyme that has important roles in lipid metabolism in liver and intestine.

  • The lipogenic activity of hepatic LXRα is a major limitation for the development of LXR agonists as therapeutics for atherosclerosis or Alzheimer disease.

  • Further basic and translational research is needed to develop novel strategies for manipulating LXRs and their targets in the setting of metabolic disease.

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Fig. 1: LXRs are lipid-responsive transcription factors.
Fig. 2: LXR signalling pathways in cholesterol and fatty acid metabolism.
Fig. 3: Roles of LXR-dependent phospholipid remodelling in liver.
Fig. 4: LPCAT3 and phospholipid remodelling in lipid absorption and intestinal homeostasis.

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  1. Department of Pathology and Laboratory Medicine, Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

    Bo Wang & Peter Tontonoz

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B.W. and P.T. discussed the content, researched the data and contributed to writing the article and to reviewing and/or editing of the manuscript before submission.

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Wang, B., Tontonoz, P. Liver X receptors in lipid signalling and membrane homeostasis. Nat Rev Endocrinol 14, 452–463 (2018). https://doi.org/10.1038/s41574-018-0037-x

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