2. Academic Validation
  3. Lipin-1 restrains macrophage lipid synthesis to promote inflammation resolution

Lipin-1 restrains macrophage lipid synthesis to promote inflammation resolution

  • bioRxiv. 2023 Oct 25:2023.10.23.563587. doi: 10.1101/2023.10.23.563587.
Temitayo T Bamgbose 1,  Robert M Schilke 1,  Oluwakemi O Igiehon 1,  Ebubechukwu H Nkadi 1,  David Custis 2,  Sushma Bharrhan 3,  Benjamin Schwarz 4,  Eric Bohrnsen 4,  Catharine M Bosio 5,  Rona S Scott 1 3,  Arif Yurdagul Jr 6,  Brian N Finck 7,  Matthew D Woolard 1 3
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA, United States.
  • 2 Research Core Facility, Louisiana State University Health Sciences Center, Shreveport, LA, United States.
  • 3 Center for Applied Immunology and Pathological Processes (CAIPP), Louisiana State University Health Sciences Center, Shreveport, LA, United States.
  • 4 Proteins & Chemistry Section, Research and Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Disease, Hamilton, MT.
  • 5 Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Disease, Hamilton, MT.
  • 6 Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, Shreveport, LA, United States.
  • 7 Division of Nutritional Sciences and Obesity Medicine, Washington University School of Medicine, St. Louis, MO, United States.
PMID: 37961352 DOI: 10.1101/2023.10.23.563587
Abstract

Macrophages are critical to maintaining and restoring tissue homeostasis during inflammation. The lipid metabolic state of macrophages influences their function, but a deeper understanding of how lipid metabolism is regulated in pro-resolving macrophage responses is needed. Lipin-1 is a phosphatidic Acid Phosphatase with a transcriptional coregulatory activity (TC) that regulates lipid metabolism. We previously demonstrated that lipin-1 supports pro-resolving macrophage responses, and here, myeloid-associated lipin-1 is required for inflammation resolution, yet how lipin-1-regulated cellular mechanisms promote macrophage pro-resolution responses is unknown. We demonstrated that the loss of lipin-1 in macrophages led to increased free fatty acid, neutral lipid, and ceramide content and increased phosphorylation of Acetyl-CoA Carboxylase. The inhibition of the first step of lipid synthesis and transport of citrate from the mitochondria in macrophages reduced lipid content and restored efferocytosis and inflammation resolution in lipin-1mKO macrophages and mice. Our findings suggest macrophage-associated lipin-1 restrains lipid synthesis, promoting pro-resolving macrophage function in response to pro-resolving stimuli.

Keywords

Lipin-1; beta-oxidation; citrate; citrate carrier; efferocytosis; fatty acid; inflammation resolution; lipid metabolism; lipid synthesis; macrophage; metabolism; pro-resolving.

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