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The in vivo role of Cpt1a and whether a HFD renders ISCs, progenitors or established tumors metabolically reliant on fatty acid oxidation for their maintenance
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre. Koch Institute for Integrative Cancer Research, M.I.T..
2019 (English)Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
Abstract [en]

The mammalian intestine is made of the small intestine and the colon. The small intestine is arranged into two fundamental structures called villi and crypts. Lgr5+ cells represent the intestinal stem cells (ISCs) and are identified by marker gene Lgr5, which is expressed at the bottom of mouse crypts, i.e. mucosal glands found in the intestinal epithelium. The mammalian intestine is said to respond to signals from the diet. Increased ISC numbers and progenitor proliferation have been associated with the effects of a high-fat diet (HFD) and these cells can, under HFD conditions initiate organoids i.e. small intestine-like structures cultured in vitro. In relation to cancer it has been shown that a HFD acts through the nuclear receptor PPAR-δ in ISCs and progenitors, and that PPAR-δ is also involved in fatty acid oxidation (FAO) as a master transcriptional regulator of the key FAO gene Cpt1a. The aim of this Master’s thesis seeks to assess whether a HFD renders ISCs, progenitors or established tumors metabolically reliant on FAO for their maintenance. Lineage tracing analysis in vivo with the computer software Aperio ImageScope, after βgalactosidase staining experiments contributed to confirm the reduced effects of a HFD in ISCs and progenitors as consequence of Cpt1a loss. The inhibition of FAO through in vitro and in vivo organoid experiments with genotypes APCΔ; P53Δ; Rosa-LSL-ZsGreen; Vil-CreER (APZV) and APCΔ; P53Δ; Cpt1afl/fl; Rosa-LSL-tdTomato; Vil-CreER (APCTV) also showed adverse effects on tumor maintenance. This from the clonogenicity assay after cell/organoid count analysis with the computer software ImageJ. In conclusion from the results obtained, which confirmed the hypothesis in the aims to a large extent Cpt1a could serve as a potential future therapeutic target. However, more experimental trials are needed to ascertain whether Cpt1a is the main contributor to mediate the HFD phenotype, but it is a promising start in the right direction. Increased knowledge of the impacts of diet in health and disease pursues to assist both in the prevention, as well as in the cure of established diseases in patients such as cancer. In the future, it would also be of interest to focus on and confirm whether the effects of the diet on various pathologies is reversible.

Place, publisher, year, edition, pages
2019. , p. 26
Keywords [en]
Health and nutrition, Diet-induced obesity, Palmitic acid, Organoids, Lgr5+ intestinal stem cells, Stem cell Biology, Cancer
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:uu:diva-377913OAI: oai:DiVA.org:uu-377913DiVA, id: diva2:1292336
Educational program
Master Programme in Molecular Biotechnology
Supervisors
Examiners
Available from: 2019-03-01 Created: 2019-02-27 Last updated: 2019-03-01Bibliographically approved

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