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Anti-atherogenic actions of dihomo-gamma-linolenic acid in macrophages

Gallagher, Hayley 2016. Anti-atherogenic actions of dihomo-gamma-linolenic acid in macrophages. PhD Thesis, Cardiff University.
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Abstract

Atherosclerosis is a chronic inflammatory disorder characterised by lipid accumulation in the arterial wall. Nutraceuticals represent promising alternatives to pharmaceuticals in the prevention and management of this disease. Previous work has shown an omega-6 fatty acid, dihomo-gamma-linolenic acid (DGLA) to inhibit atherosclerosis in a mouse model of the disease. Understanding the molecular mechanism underlying the action of DGLA in atherosclerosis is crucial to evaluating the role of this PUFA as a new agent in the prevention/treatment of the disease. In vitro analysis utilised macrophage cell lines THP-1 and RAW264.7 together with primary cultures of human monocyte-derived macrophages to study the effects of DGLA on aspects of macrophage foam cell formation, an early event in atherosclerosis. Data presented in the thesis showed that DGLA had an effect on a number of key events that contribute to foam cell formation in macrophages; reducing monocyte migration, pro-inflammatory cytokine induced gene expression, modified LDL uptake, scavenger receptor expression, macropinocytosis and cholesteryl ester accumulation and stimulating cholesterol efflux. Uptake of DGLA into lipid fractions was studied in vitro and in vivo using thin layer chromatography and gas chromatography. DGLA was significantly incorporated in a dose-dependent manner into lipid fractions of THP-1 macrophages in vitro. In vivo, mice fed a 4.4% DGLA containing diet assimilated the PUFA into serum, liver, kidney and adipose tissue lipid fractions. Finally, the metabolism of DGLA was investigated in vitro. DGLA supplementation stimulated the production of PGE1 and 15-HETrE in macrophages. PGE1 inhibited monocyte migration and IFN-γ induced expression of monocyte chemotactic protein 1 (MCP-1). RNA interference assays showed a key role for COX enzymes in the IFN-γ-mediated induction of MCP-1 expression. Findings in the thesis demonstrate key mechanisms underlying the anti-atherogenic role of DGLA and highlight its potential as a therapeutic/preventative agent in this disease.

Item Type: Thesis (PhD)
Date Type: Publication
Status: Unpublished
Schools: Biosciences
Subjects: R Medicine > R Medicine (General)
Date of First Compliant Deposit: 14 July 2016
Last Modified: 28 Jun 2019 02:05
URI: http://orca.cf.ac.uk/id/eprint/92567

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