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Title: Investigating acute gastrointestinal inflammation associated with feeding a fat-enriched diet in zebrafish larvae
Author: Sangha, Navjyot Singh
ISNI:       0000 0004 2732 2245
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Diseases of the metabolic syndrome such as obesity, type II diabetes and atherosclerosis are caused by an excess accumulation of dietary lipid and are currently a major burden on healthcare. The NLRP3 inflammasome is a molecular platform that leads to activation of caspase-1 and has received considerable attention recently regarding its role in promoting the inflammation associated with these diseases. The chronic inflammation associated with these states is well understood but the acute inflammation has not been investigated in detail and is the focus of this study. The zebrafish innate immune system functions in a similar manner to that of mammals and the uptake of dietary fat in the gastrointestinal tract is also strongly conserved. Thus, using zebrafish larvae, a model of acute gastrointestinal inflammation following feeding on a fat-enriched diet has been established and characterised. Additionally, the role of the NLRP3 inflammasome in the inflammation associated with feeding on such a diet has been investigated using pharmacological inhibitors and morpholino knockdown of components of this pathway. The results demonstrate that larvae fed a cholesterol-enriched diet for 6h develop localized inflammation in the intestine as illustrated by the recruitment of myeloid cells to this region 18h following removal from the diet. Feeding on a diet enriched in palmitic acid also achieves this effect, whilst an unsaturated fatty acid-enriched diet does not. Reverting to a standard diet following feeding on a cholesterol-enriched diet resolves the localised recruitment of immune cells to the intestine. Treatment with inhibitors targeting several components of the NLRP3 inflammasome blocks the recruitment of inflammatory cells to the intestines of larvae fed a cholesterol-enriched diet, as does treatment with a splice-blocking morpholino against ASC, which is necessary for caspase-1 activation. The results thus suggest that the acute inflammation in the intestine associated with feeding on a cholesterol-enriched diet is at least in part dependent on the NLRP3 inflammasome.
Supervisor: Dallman, Maggie Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral