Investigation of the control mechanisms regulating fatty acid availability during infection.

Hampton, Katherine Jane (2025) Investigation of the control mechanisms regulating fatty acid availability during infection. Doctoral thesis, University of East Anglia.

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Abstract

During infection, hematopoietic stem and progenitor cells (HSPCs) rapidly expand to coordinate an effective immune response. Fatty acid uptake and metabolism are central to providing sufficient energy for HSPC expansion. However, the mechanisms that drive these changes are unknown. This study investigates the regulation of fatty acid availability to support this HSPC expansion.

Within 6 hours of lipopolysaccharide (LPS) administration, liver fatty acid uptake and metabolism was significantly downregulated. This downregulation was associated with a significant increase in circulating long-chain fatty acids (LCFAs). In vitro assays using hepatocytes demonstrated that circulating cytokines released in response to LPS caused this downregulation. Of these cytokines, only Plasminogen activator inhibitor-1 (PAI-1) significantly decreased LCFA uptake and metabolism in hepatocytes. Pharmacological inhibition of PAI-1 using TM5441 prevented the downregulation of hepatic fatty acid metabolism both in vitro and in vivo, resulting in a reduction in the availability of circulating LCFAs in response to LPS. Subsequently, pre-treating mice with TM5441 prior to LPS injection resulted in a significant reduction in HSC expansion normally seen in response to LPS.

Up to 90% of PAI-1 is stored in platelets. This thesis provides evidence that platelets can rapidly release PAI-1 in response to LPS. Depleting platelets from mice prior to LPS treatment significantly reduced the downregulation of liver fatty acid metabolism, reducing circulating LCFAs. Taken together, findings demonstrate that circulating LCFAs increase in response to infection to support immune cell expansion. Increased circulating LCFAs is at least partly driven by PAI-1 released from platelets, downregulating liver LCFA uptake and metabolism, allowing LCFAs to remain in circulation necessary to fuel HSC expansion during emergency haematopoiesis

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User:	Chris White
Date Deposited:	21 Oct 2025 08:02
Last Modified:	21 Oct 2025 08:02
URI:	https://ueaeprints.uea.ac.uk/id/eprint/100727
DOI:

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