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Amer, Abeer HA (2011) Mechanism of Action of Liver Growth Amer, Abeer H. A. (2011) Mechanism of action of liver growth induced by peroxisome proliferators. PhD thesis, University of Nottingham. Access from the University of Nottingham repository: http://eprints.nottingham.ac.uk/11947/1/Abeer_Amer_PhD_Thesis_17_feb_11.pdf Copyright and reuse: The Nottingham ePrints service makes this work by researchers of the University of Nottingham available open access under the following conditions. · Copyright and all moral rights to the version of the paper presented here belong to the individual author(s) and/or other copyright owners. · To the extent reasonable and practicable the material made available in Nottingham ePrints has been checked for eligibility before being made available. · Copies of full items can be used for personal research or study, educational, or not- for-profit purposes without prior permission or charge provided that the authors, title and full bibliographic details are credited, a hyperlink and/or URL is given for the original metadata page and the content is not changed in any way. · Quotations or similar reproductions must be sufficiently acknowledged. Please see our full end user licence at: http://eprints.nottingham.ac.uk/end_user_agreement.pdf A note on versions: The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher’s version. Please see the repository url above for details on accessing the published version and note that access may require a subscription. For more information, please contact [email protected] Mechanism of Action of Liver Growth Induced by Peroxisome Proliferators by Abeer H. A. Amer B.Sc., M.Sc. Thesis submitted to The University of Nottingham for the degree of Doctor of Philosophy 17th Febuary 2011 In The Name Of God (Allah) The Most Merciful The Most Gracious Abeer Amer Abstract Humans are ubiquitously exposed to peroxisome proliferators including hypolipidemic agents, industrial solvents and natural products. Because of this and the fact that peroxisome prolifera- tors cause non-genotoxic hepatocarcinogenesis in rodents, it is of importance to elucidate the mechanism of action of the peroxisome proliferators in order to provide an assessment of the hazard, if any, of these compounds to humans. It is also known that the peroxisome proliferators begin their actions by inducing hepatic DNA synthesis. Thus, the aim of this thesis was to find genes that could be responsible for triggering the induction of hepatic DNA synthesis caused by peroxisome proliferators, specifically ciprofibrate. First, it was important to indicate when the induction of hepatic DNA synthesis actually hap- pens. This was done with BrdU immunohistochemical procedures. The induction of hepatic DNA synthesis with ciprofibrate in mice was observable only after 4 days making it difficult to specify when the induction actually happened. In rats the induction of hepatic DNA synthesis was found to peak at 24 hours and this system gave the better opportunity to find the genes re- sponsible. The difference in the timing of induced hepatic DNA synthesis between mice and rats implied that there could be a species difference in the mechanism of each species’ response to PPAR. With immunohistochemistry it was noticed that there was a difference in the lobular lo- calization of hepatic DNA synthesis in the liver tissues of rats and mice dosed with different inducers, with the rat livers exhibiting periportal distribution while hepatic DNA synthesis in the mice seemed to be distributed throughout the liver tissue. The effects of ciprofibrate or cyproterone acetate on liver gene expression in rats were studied, using cDNA microarrays, transcriptome sequencing and quantitative real- time PCR. A 1- 5 hour treatment period was chosen to detect the immediate early gene response, while a 24 hour time point was chosen to elucidate the confounding effects from the hepatic DNA synthesis seen Page 1 Abeer Amer during the 24 hour stimulation. The results showed that ciprofibrate altered the expression of numerous genes including previously known PPARα agonist-responsive genes involved in pro- cesses such as PPAR signalling pathways, fatty acid metabolic pathway, cell cycle, palmitoyl- CoA hydrolase activity, lipid metabolism, inflammatory responses, and stress responses, in ad- dition to a large number of novel candidate genes. Three novel induced genes G0s2, Ccnd1 and Scd1, (and two marker genes CYP4A1 and CYP3A1) were confirmed with quantitative real- time PCR. The G0s2, Ccnd1 and Scd1 were found to be up-regulated at the hours 1 and 3 after dosing and not 24 hours, and the G0s2 and Scd1 were specific for the ciprofibrate suggesting they were involved in a distinct PPARα path- way responsible for the hepatic DNA synthesis. The complete database of the transcriptional response provided here opens doors of opportunity for further research to identify genes respon- sible for the liver growth induced by peroxisome proliferators. Page 2 Abeer Amer Acknowledgments I can not thank enough my former supervisor, Dr David Bell who supervised me for over 3 years for his advice and guidance. Even after he left he was always happy to support me and to reply to my e-mails even on his holidays! He will always be my role model for his passion about sci- ence and his dedication to his students and work. I would also like to thank my supervisor Dr Simon Avery for his help in correcting my thesis and whose advice and encouragement got me through to the end of my PhD. I would like to thank Dr Abdullah Al-kholaifi for his instructions and help with the immunohis- tochemistry and for his generosity with his slides that gave me the insight to explore and study. I would like to show my gratitude to Dr Tim Gant from Leisecter University for allowing me to use his microarray scanner and for his help with the analysis, and to Kate Phillips for providing me with the microarray slides and for training me to use the microarray scanner. I would also like to show my appreciation to Dr Aboobaker Aziz from the University of Nottingham QMC for his help with the transcriptome analysis, and for letting me take over his computer for the duration of my work in his lab. I especially would like to thank Richard Wall and Himanshu Kharkwal who were a great help in training me to conduct and analyse the qRT-PCR, and for all the BBQs and meals they were always keen on organizing for the group. And a big thank you to Mr. Declan Brady who was always there for help and advice. Finally, I would like to thank the Libyan people for providing financial support for my study and thank you to all my family and friends for their help and support in making this PhD a plea- surable time of my life. Page 3 Abeer Amer Dedication Thisthesisisdedicatedto myMotherandFather,myHusbandWailandtomyChildren Monder,Alaaand Mohammed Thisthesisisdedicatedto thememoryof mygrandfatherAyad Amer andtothe Martyrs of the Libyan Cause Page 4 Abeer Amer Declaration I declare, that this work was achieved in the duration of my PhD studies at the Uni- versity of Nottingham, and is my original effort unless otherwise stated. Informa- tion from other resources has been fully recognized. No part of this thesis has been submitted for assessment leading to a degree. Abeer Amer 17th Febuary 2011 Page 5 Abeer Amer TABLE OF CONTENTS Abstract .................................................................................................................................. 1 Acknowledgments.................................................................................................................. 3 Dedication .............................................................................................................................. 4 Declaration ............................................................................................................................. 5 Table of contents.................................................................................................................... 6 List of figures ......................................................................................................................... 1 0 List of tables............................................................................................................................ 1 2 Presentations and publications arising from this thesis........................................................ 13 List of Abbreviations............................................................................................................ 14 1 Introduction ........................................................................................................................ 18 1.1 The Liver......................................................................................................................... 18 1.1.1 Histology and physiology of the liver.......................................................................... 18 1.1.2 Liver regeneration (growth) ......................................................................................... 22 1.1.3 Basic characteristics of liver regeneration ................................................................... 23 1.2 Peroxisome proliferation................................................................................................. 25 1.2.1 Peroxisomes ................................................................................................................. 25 1.2.2 Peroxisome proliferators (PPs)....................................................................................
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