Inflammation Triggers Liver X Receptor-Dependent Lipogenesis

ABSTRACT

Immune cell function can be modulated by changes in lipid metabolism. Our studies indicate that cholesterol and fatty acid synthesis increases in macrophages between 12 and 18 h after the activation of Toll-like receptors with proinflammatory stimuli and that the upregulation of lipogenesis may contribute to the resolution of inflammation. The inflammation-dependent increase in lipogenesis requires the induction of the liver X receptors, members of the nuclear receptor superfamily of transcription factors, by type I interferons in response to inflammatory signals. Instead of the well-established role for liver X receptors in stimulating cholesterol efflux, we demonstrate that liver X receptors are necessary for the proper resumption of cholesterol synthesis in response to inflammatory signals. Thus, liver X receptors function as bidirectional regulators of cholesterol homeostasis, driving efflux when cholesterol levels are high and facilitating synthesis in response to inflammatory signals. Liver X receptor activity is also required for the proper shutdown of a subset of type I interferon-stimulated genes as inflammation subsides, placing the receptors in a negative-feedback loop that may contribute to the resolution of the inflammatory response.

KEYWORDS:

• inflammation
• lipids
• transcription
• macrophage
• nuclear receptor
• lipid synthesis
• transcriptional regulation

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ACKNOWLEDGMENTS

This work was supported by a grant from the NIH/NHLBI (HL48044) to T.F.O. and by grants from the NIH/NIDDK (1R01DK119182-01A) and the American Heart Association (15GRNT25560038) to I.G.S.

We thank Norbert Leitinger and Thurl Harris for comments on the manuscript.