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Permanent link (DOI): https://doi.org/10.7939/R36060

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Insights into the role of CTP:phosphocholine cytidylyltransferase-alpha in hepatic lipid metabolism and cellular integrity Open Access

Descriptions

Other title
Subject/Keyword
Phosphatidylcholine
ChoK1
Ceramide
CTP:phosphocholine cytidylyltransferase
Non-alcoholic steatohepatitis
Phosphatidylethanolamine
Apoptosis
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Niebergall, Lorissa J
Supervisor and department
Vance, Dennis E. (Biochemistry)
Examining committee member and department
Goping, Ing Swie (Biochemistry)
Mallampalli, Rama (University of Pittsburg, Cell Biology and Physiology)
Holmes, Charles (Biochemistry)
Mason, Andrew (Medicine)
Department
Department of Biochemistry
Specialization

Date accepted
2011-09-27T19:44:40Z
Graduation date
2011-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Lower levels of hepatic phosphatidylcholine (PC) are suggested to play a role in the pathogenesis of non-alcoholic steatohepatitis (NASH). Mice lacking hepatic CTP:phosphocholine cytidylyltransferase-α (LCTα-/-), the regulatory enzyme in the CDP-choline pathway for PC biosynthesis, were fed a high fat diet to investigate the role of impaired PC biosynthesis in the pathogenesis of NASH. CTα-deficient livers developed moderate NASH within one week of high fat feeding. In addition, LCTα deficiency caused a 2-fold increase in hepatic levels of ceramide, and a 20% decrease in hepatic PC mass. Although stimulation of PC biosynthesis prevented hepatic steatosis, normalization of hepatic PC did not prevent either hepatic ceramide accumulation, or the development of NASH. These data indicate that impaired PC biosynthesis does not play a direct role in the transition from steatosis to NASH. Although reduced cellular PC induces apoptosis, a lower PC to phosphatidylethanolamine (PE) ratio has been demonstrated to influence membrane integrity, causing NASH. To investigate whether a reduced PC:PE ratio, rather than reduced cellular PC, influences membrane integrity, we utilized mutant 58 (MT58) Chinese hamster ovary cells. After incubation at the restrictive temperature, MT58 cells showed a 2-fold reduction in cellular PC and in the PC:PE ratio, leading to cellular death. In an attempt to normalize the PC:PE ratio and stabilize cellular membranes, MT58 cells were treated with silencing RNA to inhibit PE biosynthesis. However, inhibition of PE biosynthesis caused a 30% reduction in cellular PE and PC masses, and therefore, did not normalize the PC:PE ratio. Moreover, MT58 cells showed a further loss of membrane integrity after knockdown of PE biosynthesis. Treatment of MT58 cells with lysophosphatidylcholine normalized cellular PC mass and prevented cellular death. However, lysophosphatidylcholine treatment caused an increase in PE mass, and therefore, did not normalize the PC:PE ratio. These data show that manipulation of the PC:PE ratio will not rescue MT58 cells from cell death since cellular growth and integrity are influenced by the total amount of cellular PC and PE, and not by the PC:PE ratio. In summary, these studies outline the importance of CTα in maintaining cellular integrity and hepatic lipid metabolism.
Language
English
DOI
doi:10.7939/R36060
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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