Intestinal inflammation requires FOXO3 and prostaglandin E2-dependent lipogenesis and elevated lipid droplets.

Abstract

Intestinal inflammation has been recently characterized by the dysregulation of lipids as metabolic and energy sources, revealing a novel feature of its pathophysiology. Because intracellular lipids, stored in dynamic lipid droplets (LDs), provide energy for cellular needs, we investigated whether they play a role in intestinal inflammation. In the inflamed intestine of mice, elevated LDs were found in colonic and infiltrating immune cells as shown by staining for the LD coat protein PLIN2 and for lipids with BODIPY. In colonic cells, TNF stimulated LD increases by receptor signaling rely on phosphatidylinositol 3-kinase activation. Downstream, TNF triggered a negative regulatory loop between LDs and the transcription factor FOXO3. This was shown in the colon of Foxo3-deficient mice, where elevation in PLIN2 and lipids were further facilitated by inflammation and were more prominent relative to wild-type, whereas, in colonic cells, inhibition of lipogenesis blocked the TNF-mediated loss of FOXO3. Furthermore, blockade of PGE2 synthesis abrogated TNF-stimulated increases in LDs and FOXO3 inactivation. We found in colonic tissue of Foxo3-deficient mice higher levels of cyclooxygenase-2, a mediator of prostaglandin E2 (PGE2) synthesis, supporting involvement of PGE2 in the LD-FOXO3 regulatory loop. Ultimately, TNF-stimulated lipogenesis leading to elevated LDs facilitated NF-κB-mediated increases in IL-8 protein, which is associated with the surface of LDs found in the lumina of the endoplasmic reticulum and Golgi apparatus. This novel immunometabolic mechanism of colonic inflammation involving elevated LDs could provide opportunities for new treatment options.

• Authors: Sandra Heller, Chloe Cable, Harrison Penrose, Rania Makboul, Debjani Biswas, Maleen Cabe, Susan E Crawford, Suzana D Savkovic
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 310 Issue 10 Pg. G844-54 (05 15 2016) ISSN: 1522-1547 [Electronic] United States
• PMID: 26968210 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 the American Physiological Society.

Chemical References

• Forkhead Box Protein O3
• FoxO3 protein, mouse
• Interleukin-8
• Perilipin-2
• Plin2 protein, mouse
• Tumor Necrosis Factor-alpha
• Dinoprostone

Topics

• Animals
• Dinoprostone (metabolism)
• Endoplasmic Reticulum (metabolism)
• Forkhead Box Protein O3 (genetics, metabolism)
• Golgi Apparatus (metabolism)
• HCT116 Cells
• HT29 Cells
• Humans
• Inflammation (metabolism)
• Interleukin-8 (metabolism)
• Intestinal Mucosa (drug effects, metabolism)
• Lipid Droplets (metabolism)
• Lipogenesis
• Mice
• Mice, Inbred C57BL
• Perilipin-2 (metabolism)
• Tumor Necrosis Factor-alpha (pharmacology)