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dc.contributor.authorJenkins, Benjamin John
dc.date.accessioned2018-07-11T11:52:32Z
dc.date.available2018-07-11T11:52:32Z
dc.date.issued2018-10-22
dc.date.submitted2017-09-20
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/278025
dc.description.abstractRecent findings have shown an inverse association between the circulating levels of pentadecanoic acid (C15:0) and heptadecanoic acid (C17:0) with the risk of pathological development in type 2 diabetes, cardio vascular disease and neurological disorders. From previously published research, it has been said that both these odd chain fatty acids are biomarkers of their dietary intake and are significantly correlated to dietary ruminant fat intake. However, there are profound studies that show the contrary where they do not display this biomarker correlation. Additionally, several astute studies have suggested or shown odd chain fatty acid endogenous biosynthesis, most often suggested via alpha oxidation; the cleavage of a single carbon unit from a fatty acid chain within the peroxisomes. To better understand the correlations and interactions between these two fatty acids with pathological development, the origin of these odd chain fatty acids needed to be determined, along with confirming their association with the disease aetiology. To minimise animal & human experimentation we made use of existing sample sets made available through institutional collaborations, which produced both animal and human interventional study samples suitable for odd chain fatty acid investigations. These sample collaborations allowed us to comprehensively investigate all plausible contributory sources of these odd chain fatty acids; including from the intestinal microbiota, from dietary contributions, and derived from novel endogenous biosynthesis. The investigations included two intestinal germ-free studies, two ruminant fat diet studies, two dietary fat studies and an ethanol intake study. Endogenous biosynthesis was assessed through: a stearic acid infusion, phytol supplementation, and an Hacl1 knockout mouse model. A human dietary intervention study was used to translate the results. Finally, a study comparing circulating baseline C15:0 and C17:0 levels with the development of glucose intolerance. We found that the circulating C15:0 and C17:0 levels were not significantly influenced by the presence or absence of intestinal microbiota. The circulating C15:0 levels were significantly and linearly increased when the C15:0 dietary composition increased; however, there was no significant correlation in the circulating C17:0 levels with intake. Circulating levels of C15:0 were affected by the dietary composition and factors affecting the dietary intake, e.g. total fat intake and ethanol, whereas circulating C17:0 levels were found to be independent of these variables. In our studies, the circulating C15:0 levels were not significantly affected by any expected variations in alpha oxidation caused by pathway substrate inhibition or gene knockout. However, C17:0 was significantly related, demonstrating it is substantially endogenously biosynthesised. Furthermore, we found that the circulating C15:0 levels, when independent of any dietary variations, did not correlate with the progression of glucose intolerance when induced, but the circulating C17:0 levels did significantly relate and linearly correlated with the development of glucose intolerance. To summarise, the circulating C15:0 and C17:0 levels were independently derived; the C15:0 levels substantially correlated with its dietary intake, whilst the C17:0 levels proved to be separately derived from its endogenous biosynthesis via alpha oxidation of stearic acid. C15:0 was found to be minimally endogenously biosynthesised via a single cycle of beta oxidation of C17:0 in the peroxisomes, however, this did not significantly contribute to the circulating levels of C15:0. Additionally, only the baseline levels of C17:0 significantly correlated with the development of glucose intolerance. These findings highlight the considerable differences between both of these odd chain fatty acids that were once thought to be homogeneous and similarly derived. On the contrary, they display profound dietary, metabolic, and pathological differences.
dc.description.sponsorshipMedical Research Council
dc.language.isoen
dc.rightsAll rights reserved
dc.rightsAll Rights Reserveden
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved/en
dc.subjectPentadecanoic acid
dc.subjectheptadecanoic acid
dc.subjectC15:0
dc.subjectC17:0
dc.subject15:0
dc.subject17:0
dc.subjectOdd chain fatty acids
dc.subjectAlpha oxidation
dc.subjectBiomarker
dc.subjectDietary biomarker
dc.subjectRuminant fat
dc.subjectHACL1
dc.subjectBeta oxidation
dc.subjectDairy fat
dc.subjectGlucose intolerance
dc.subject2-hydroxy-acyl CoA lyase
dc.subjectBranched chain fatty acids
dc.subjectBeta-branched chain fatty acids
dc.subjectStearic acid
dc.subjectPeroxisomes
dc.titleTHE ROLE OF ALPHA OXIDATION IN LIPID METABOLISM
dc.typeThesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnameDoctor of Philosophy (PhD)
dc.publisher.institutionUniversity of Cambridge
dc.publisher.departmentMRC Elsie Widdowson Laboratory
dc.date.updated2018-07-10T20:59:42Z
dc.identifier.doi10.17863/CAM.25351
dc.publisher.collegeDarwin college
dc.type.qualificationtitlePhD in Biochemistry
cam.supervisorKoulman, Albert
cam.thesis.fundingfalse
rioxxterms.freetoread.startdate2019-07-11


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