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Regulation of Vitamin D Metabolism by Metabolic State in Mice and Humans

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Regulation of Vitamin D Metabolism by Metabolic State in Mice and Humans D 1575 OULU 2020 D 1575 UNIVERSITY OF OULU P.O. Box 8000 FI-90014 UNIVERSITY OF OULU FINLAND ACTA UNIVERSITATIS OULUENSIS ACTA UNIVERSITATIS OULUENSIS ACTA DMEDICA Mahmoud Sobhy Elkhwanky Mahmoud Sobhy Elkhwanky Mahmoud Sobhy University Lecturer Tuomo Glumoff REGULATION OF VITAMIN D University Lecturer Santeri Palviainen METABOLISM BY METABOLIC Postdoctoral researcher Jani Peräntie STATE IN MICE AND HUMANS DISCOVERY OF MOLECULAR FACTORS REPRESSING University Lecturer Anne Tuomisto VITAMIN D BIOACTIVATION AND INDUCING DEFICIENCY IN DIABETES University Lecturer Veli-Matti Ulvinen Planning Director Pertti Tikkanen Professor Jari Juga University Lecturer Anu Soikkeli University Lecturer Santeri Palviainen UNIVERSITY OF OULU GRADUATE SCHOOL; UNIVERSITY OF OULU, FACULTY OF MEDICINE; Publications Editor Kirsti Nurkkala MEDICAL RESEARCH CENTER OULU; BIOCENTER OULU ISBN 978-952-62-2641-5 (Paperback) ISBN 978-952-62-2642-2 (PDF) ISSN 0355-3221 (Print) ISSN 1796-2234 (Online) ACTA UNIVERSITATIS OULUENSIS D Medica 1575 MAHMOUD SOBHY ELKHWANKY REGULATION OF VITAMIN D METABOLISM BY METABOLIC STATE IN MICE AND HUMANS Discovery of molecular factors repressing vitamin D bioactivation and inducing deficiency in diabetes Academic dissertation to be presented with the assent of the Doctoral Training Committee of Health and Biosciences of the University of Oulu for public defence in Auditorium F202 of the Faculty of Medicine (Aapistie 5 B), on 29 May 2020, at 12 noon UNIVERSITY OF OULU, OULU 2020 Copyright © 2020 Acta Univ. Oul. D 1575, 2020 Supervised by Professor Jukka Hakkola Reviewed by Professor Roger Bouillon Professor Carsten Carlberg Opponent Associate Professor Enikö Kallay ISBN 978-952-62-2641-5 (Paperback) ISBN 978-952-62-2642-2 (PDF) ISSN 0355-3221 (Printed) ISSN 1796-2234 (Online) Cover Design Raimo Ahonen PUNAMUSTA TAMPERE 2020 Elkhwanky, Mahmoud Sobhy, Regulation of vitamin D metabolism by metabolic state in mice and humans. Discovery of molecular factors repressing vitamin D bioactivation and inducing deficiency in diabetes University of Oulu Graduate School; University of Oulu, Faculty of Medicine; Medical Research Center Oulu; Biocenter Oulu Acta Univ. Oul. D 1575, 2020 University of Oulu, P.O. Box 8000, FI-90014 University of Oulu, Finland Abstract Vitamin D deficiency, i.e., low circulating 25-hydroxyvitamin D (25(OH)D) level, has been consistently associated with the prevalence of metabolic diseases, including types 1 and 2 diabetes. However, the causal link between low vitamin D and metabolic disturbances remains uncertain. In the present thesis, I report novel findings indicating that vitamin D metabolism is under strict control by the metabolic state. Specifically, obesity represses the expression of cytochrome P450 (CYP) 2R1, the major vitamin D 25-hydroxylase responsible for the first bioactivation step in both mice and humans. Interestingly, in humans, weight loss induced by gastric bypass surgery increased CYP2R1 expression in the white adipose tissue. In mouse liver, Cyp2r1 and vitamin D bioactivation was suppressed by fasting, and both type 1 and type 2 diabetes. This may consequently cause low plasma 25(OH)D levels. On the other hand, fasting induced expression of the vitamin D catabolic enzyme CYP24A1 in the kidney. Mechanistically, we discovered that Cyp2r1 and vitamin D bioactivation are repressed by molecular pathways activated physiologically by fasting or pathologically in diabetes, namely, the peroxisome proliferator-activated receptor-gamma coactivator 1-α and estrogen-related receptor α (PGC-1α-ERRα), and the glucocorticoid receptor pathways. Moreover, the PGC-1α-ERRα pathway is crucial for mediating the Cyp24a1 induction by fasting in the kidney. In the current thesis, we uncover a molecular mechanism for the vitamin D deficiency observed in diabetic patients and reveal a novel negative feedback mechanism controlling the crosstalk between energy homeostasis and the vitamin D pathway. Importantly, our data propose that vitamin D deficiency is a consequence, and not the cause of diabetes. Keywords: 25-hydroxyvitamin D, adipose tissue, CYP24A1, CYP2R1, diabetes, GR, human, liver, mice, obesity, PGC-1α, vitamin D Elkhwanky, Mahmoud Sobhy, Metabolinen tila säätelee D-vitamiinin aineen- vaihduntaa hiiressä ja ihmisessä. D-vitamiinin bioaktivaatiota estävien ja puutosta aiheuttavien molekyylimekanismien osoittaminen Oulun yliopiston tutkijakoulu; Oulun yliopisto, Lääketieteellinen tiedekunta; Medical Research Center Oulu; Biocenter Oulu Acta Univ. Oul. D 1575, 2020 Oulun yliopisto, PL 8000, 90014 Oulun yliopisto Tiivistelmä D-vitamiinin puutteen eli veren matalan 25-hydroksi-D-vitamiinin (25(OH)D) pitoisuuden on havaittu toistuvasti assosioituvan metabolisten sairauksien, kuten tyypin 1 ja 2 diabeteksen, ilmenemiseen. Tästä huolimatta D-vitamiinin puutteen ja metabolisten häiriöiden välinen kausaalinen yhteys on epävarma. Tässä väitöskirjatyössä raportoimme uusia löydöksiä, jotka osoittavat elimistön metabolisen tilan tehokkaasti säätelevän D-vitamiinin aineenvaihduntaa. Tarkemmin ottaen lihavuus repres- soi sytokromi P450 (CYP) 2R1:ta, D-vitamiinin tärkeintä 25-hydroksylaasia ja ensimmäistä bio- aktivaatiovaihetta sekä hiirissä että ihmisissä. Mielenkiintoinen havainto oli, että ihmisillä maha- laukun ohitusleikkaukseen liittyvä painonlasku sai aikaan CYP2R1:n ilmenemisen nousun val- keassa rasvakudoksessa. Hiiren maksassa sekä tyypin 1 ja 2 diabetes että paastoaminen vähensi- vät Cyp2r1:n ilmentymistä ja D-vitamiinin bioaktivaatiota. Tämä voi johtaa plasman 25(OH)D pitoisuuden alentumiseen. Toisaalta paastoaminen indusoi D-vitamiinin kataboliaentsyymiä, CYP24A1, munuaisessa. Mekanistisella tasolla havaitsimme, että Cyp2r1 ilmentymistä ja D-vitamiinin bioaktivaatio- ta estävät sellaiset molekylaariset säätelytiet, jotka aktivoituvat fysiologisesti paaston aikana ja patologisesti diabeteksessa. Tällaisia ovat peroksisomi-proliferaattori-aktivaattori-reseptori γ:n koaktivaattori 1 α:n ja estrogeeniin kaltainen reseptori α:n (PGC-1α-ERRα) sekä glukokortikoi- direseptorin välittämät säätelytiet. PGC-1α-ERRα säätelee tämän lisäksi myös Cyp24a1:n induk- tiota munuaisessa paaston aikana. Tässä väitöskirjatyössä tunnistimme molekylaarisen mekanismin, joka selittää diabeetikoilla havaitun D-vitamiinin puutteen ja löysimme aiemmin tuntemattoman negatiivisen palautemeka- nismin, joka välittää energiahomeostaasin ja D-vitamiinijärjestelmän välistä vuorovaikutusta. Löydöksien perusteella voidaan tehdä tärkeä johtopäätös, että D-vitamiinin puutos on diabetek- sen seuraus, ei syy. Asiasanat: 25-hydroksi-D-vitamiini, CYP24A1, CYP2R1, D-vitamiini, diabetes, GR, liikalihavuus, maksa, maksa, PGC-1α “My education, from primary school to the doctorate level, was full of tough challenges. If I had given up in the middle, I would not be able to write these lines here. Therefore, my advice is this. Do not ever give up on your dream! Believe it, and you can do it” - Mahmoud Sobhy Elkhwanky, Oulu, 24thApril 2020 “…always be guided by the light of knowledge and wisdom to shape your future, the future of your country, and the future of the world” - Professor Ahmed Zewil (l946-2016), Egyptian-American Scientist, and Nobel laureate 1999 in Chemistry. 8 Acknowledgments First and foremost, I would like to humbly thank the Almighty God, for helping me not just in this work, but in everything in my life. This work was carried out at the Research Unit of Biomedicine (Pharmacology and Toxicology), Faculty of Medicine, University of Oulu, Finland, during the years 2015 – 2019. For this fortunate period of my life, I would like to express my most profound respect and sincerest gratitude to my supervisor Professor Jukka Hakkola. Thank you for your valuable mentorship. Your wisdom, enthusiasm, open-mindedness, dedication, and encouragement were an inspiration to me. Your insightful guidance, comments, and support during my PhD work deserves to be highly acknowledged. Jukka! You gave me the opportunity to learn and grow, for which I am forever grateful, Todella paljon kiitoksia. The thesis was thoroughly reviewed by Professor Roger Bouillon (Katholieke Universiteit Leuven, Belgium) and Professor Carsten Carlberg (University of Eastern Finland). I am grateful to them for their critical and constructive comments, which improved my final thesis significantly. I am grateful to Professor Enikö Kallay (Medical University of Vienna) for accepting to be my opponent. I also wish to thank Dr. Deborah Kaska for the expert language revision. I would like to express my most profound appreciation to my follow-up committee, Professor Olli Vuolteenaho, Professor Risto Kerkelä, and Professor Sylvain Sebert for their valuable comments, discussion of my research work and support during my PhD study. I gratefully acknowledge my coauthors, and dear colleagues, Dr. Sanna-Mari Aatsinki, Dr. Outi Kummu, Dr. Mikko Karpale, Dr. Marcin Buler, and Dr. Pirkko Viitala. Special thanks to Dr. Outi Kummu for the expert help in all the animal experiments. I owe my sincere thanks to our national and international collaborators, Professor Terhi T. Piltonen (Oulu), MD Johanna Laru (Oulu), Professor Laure Morin-Papunen (Oulu), Valtteri Rinne (Admescope), Dr. Maija Mutikainen (Kuopio), Professor Pasi Tavi (Kuopio), Professor Andras Franko (Germany), Dr. Kari T. Chambers (USA), and Professor Brian N. Fink (USA). I am incredibly grateful to Ritva Tauriainen for the very skillful technical help in my PhD as well as help in learning Finnish. I also wish to thank my fellows in my lab, Dr.
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