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The role of PNPLA3 in the development and progression of chronic liver injury

McCabe, William Albert; (2020) The role of PNPLA3 in the development and progression of chronic liver injury. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Chronic liver disease is now of great international concern due to rapidly increasing morbidity and mortality associated with the disease. There is significant evidence that carriage of the patatin-like phospholipase domain containing protein 3 (PNPLA3) risk allele, rs738409:G, plays a key role in determining risk for the development of chronic liver disease from a variety of causes. rs738409 is a common single nucleotide polymorphism which results in substitution of an isoleucine residue for methionine at position 148 of PNPLA3 (Ile148Met; I148M). However, the physiological role of PNPLA3 and the functionality of its I148M variant, are currently largely unknown. The central aim of this thesis was to investigate the biological function of PNPLA3 and elucidate the complex role that the I148M variant plays in the development and progression of liver disease. Investigation into the primary sequence of PNPLA3 was undertaken to characterise the protein and inform latter experimental design. Phylogenetic investigation revealed human PNPLA5 to share the highest homology with PNPLA3, and revealed more distant, previously undescribed relationships with the bacterial protein ExoU. A combination of expression trials and subsequent in vitro investigation into the behaviour of PNPLA3 was attempted. Despite attempts with numerous constructs, PNPLA3 remained unstable when expressed using an E. coli expression system and was not able to be produced in sufficient quantity to facilitate structural analysis. In the latter half of the thesis, both variants of PNPLA3 are investigated through in silico structural modelling and subsequent molecular dynamic simulation. The first simulation of full-length PNPLA3 is reported, revealing a more detailed description of the domain architecture of PNPLA3 and the local impact of the I148M variation. A novel disease mechanism is proposed, in which methionine at residue 148 effects the conformational stability of the PNPLA3 active site, resulting in a loss of lipase activity.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The role of PNPLA3 in the development and progression of chronic liver injury
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inst for Liver and Digestive Hlth
URI: https://discovery.ucl.ac.uk/id/eprint/10093071
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