• No results found

University of Groningen Exploring the mechanisms underlying the phenotype of MCAD deficiency with Systems Medicine Martines, Anne-Claire

N/A
N/A
Info
Downloaden
Protected

Academic year: 2021

Share "University of Groningen Exploring the mechanisms underlying the phenotype of MCAD deficiency with Systems Medicine Martines, Anne-Claire"

Copied!
276
0
0

Bezig met laden.... (Bekijk nu de volledige tekst)

Download het nu ( 276 pagina )

Hele tekst

(1)University of Groningen. Exploring the mechanisms underlying the phenotype of MCAD deficiency with Systems Medicine Martines, Anne-Claire. IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.. Document Version Publisher's PDF, also known as Version of record. Publication date: 2019 Link to publication in University of Groningen/UMCG research database. Citation for published version (APA): Martines, A-C. (2019). Exploring the mechanisms underlying the phenotype of MCAD deficiency with Systems Medicine: from computational model to mice to man. Rijksuniversiteit Groningen.. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.. Download date: 28-06-2021.

(2) Exploring the mechanisms underlying the phenotype of MCAD deficiency with Systems Medicine From computational model to mice to man. Anne-Claire M.F. Martines.

(3)         Š‡™‘”†‡• ”‹„‡†‹–Š‹•–Š‡•‹•™ƒ• ƒ””‹‡†‘—–ƒ––Š‡†‡’ƒ”–‡–‘ˆ‡†‹ƒ–”‹ •ǡ‡–‡”ˆ‘” ‹˜‡”ǡ ‹‰‡•–‹˜‡ ƒ† ‡–ƒ„‘Ž‹  ‹•‡ƒ•‡•ǡ ‹˜‡”•‹–› ‘ˆ ”‘‹‰‡ǡ –Š‡ ‡–Š‡”Žƒ†•Ǥ Š‡ ”‡•‡ƒ” Š†‡• ”‹„‡†‹–Š‹•–Š‡•‹•™ƒ•ˆ—†‡†„›–Š‡‹˜‡”•‹–›‡†‹ ƒŽ‡–‡” ”‘‹‰‡ǤŠ‡ ”‡•‡ƒ” Š‰”‘—’’ƒ”–‹ ‹’ƒ–‡•‹–Š‡ ”‘‹‰‡

(4) •–‹–—–‡ˆ‘””—‰š’Ž‘”ƒ–‹‘ȋ 

(5) ȌǤ Š‡ƒ—–Š‘”‰”ƒ–‡ˆ—ŽŽ›ƒ ‘™Ž‡†‰‡•–Š‡ˆ‹ƒ ‹ƒŽ•—’’‘”–ˆ‘”’”‹–‹‰–Š‹•–Š‡•‹•„›ǣ. ”‘‹‰‡

(6) •–‹–—–‡ˆ‘””—‰š’Ž‘”ƒ–‹‘ȋ 

(7) ȌǤ ‹Œ•—‹˜‡”•‹–‡‹– ”‘‹‰‡ȋ— Ȍ ‹˜‡”•‹–›‡†‹ ƒŽ‡–‡” ”‘‹‰‡ȋ Ȍ Š—‹•–œ‘”‰–ȋ™™™Ǥ–Š—‹•‘–œ‘”‰–ǤŽȌ ƒ˜‘”ƒ„‹Ž‹–›ǤǤ ‡”–‹††‡Ž™‹Œ ‘‘’‡”–ƒƒ•  ‘˜‡”†‡•‹‰ǣ–—†‹‘   ‘˜‡”‡ƒ‹‰ǣŠ‡ ‘˜‡”‹•‹Š‘‘”‘ˆƒŽŽ™Š‘ ‘–”‹„—–‡’ƒ••‹‘ƒ–‡Ž›–‘‰ƒ‹‘”‡‹•‹‰Š– ‹–‘†‡ˆ‹ ‹‡ ›–‘Š‡Ž’ƒŽŽǦ†‡ˆ‹ ‹‡–‹†‹˜‹†—ƒŽ•Ž‹˜‡ƒˆ—ŽŽ‡”Ž‹ˆ‡Ǥ ”‘–‡‹ ƒ† ‡–ƒ„‘Ž‹–‡ ‹ƒ‰‡• ‘ –Š‡ „ƒ  ‘˜‡” ƒ”‡ ˆ”‘ —„ Š‡ ȋΪ ƒ† ƒ ›ŽǦ ƒ”‹–‹‡•Ȍǡ ‹‹‘‘• ȋ‘‡œ›‡ Ȍ ƒ†   ȋ͵ͲͶǦ—–ƒ–  ȋ

(8) ǣ Ͷͳ͵Ȍƒ†ȋ

(9) ǣʹ

(10) Ȍǡ„‘–Š‰‡‡”ƒ–‡†™‹–Š ˜‹‡™‡”ȋ

(11) ǣʹͻͺͷͲ͹͹ͺȌȌ ƒ›‘—–ǣ‡ǦŽƒ‹”‡Ǥ Ǥƒ”–‹‡• ”‹–‡†„›ǣ‹††‡”’”‹– ȁ™™™Ǥ”‹††‡”’”‹–ǤŽ 

(12) ǣ ͻ͹ͺǦͻͶǦͲ͵ͶǦͳ͹ͻͻǦͺȋ”‹–‡†˜‡”•‹‘Ȍ ͻ͹ͺǦͻͶǦͲ͵ͶǦͳ͹ͻͺǦͳȋ‹‰‹–ƒŽ˜‡”•‹‘Ȍ  ̹ǤǤ Ǥƒ”–‹‡•ǡʹͲͳͻ ŽŽ”‹‰Š–•”‡•‡”˜‡†Ǥ‘’ƒ”–‘ˆ–Š‹•–Š‡•‹•ƒ›„‡”‡’”‘†— ‡†ǡ†‹•–”‹„—–‡†•–‘”‡†‹ƒ”‡–”‹‡˜ƒŽ •›•–‡ǡ‘”–”ƒ•‹––‡†‹ƒ›ˆ‘”‘”„›ƒ›‡ƒ•™‹–Š‘—–’”‹‘”’‡”‹••‹‘‘ˆ–Š‡ƒ—–Š‘”ǡ ‘”™Š‡”‡ƒ’’Ž‹ ƒ„Ž‡ǡ–Š‡’—„Ž‹•Š‡”Š‘Ž†‹‰–Š‡ ‘’›”‹‰Š–‘–Š‡’—„Ž‹•Š‡†ƒ”–‹ Ž‡•Ǥ.

(13) Exploring the mechanisms underlying the phenotype of MCAD deficiency with Systems Medicine From computational model to mice to man. Proefschrift. ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen op gezag van de rector magnificus prof. dr. E. Sterken en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op woensdag 10 juli 2019 om 16.15 uur. door. Anne-Claire Micheline Francisca Martines geboren op 10 oktober 1981 te Willemstad, Curaçao.

(14) Promotores Prof. dr. B.M. Bakker Prof. dr. D.J. Reijngoud. Beoordelingscommissie Prof. dr. F.J. Bruggeman Prof. dr. A.K. Groen Prof. dr. F.J. van Spronsen.

(15) This PhD thesis is dedicated to my lovely parents, Ingrid Martines-Kirindongo and Edwin Martines, and my loving husband, Amart Schoop, who have always supported me through thick and thin.

(16) Paranymfen Natasha Tearr-Marcos Aduni Mariana.

(17) CONTENTS Chapter 1. Chapter 2. Chapter 3. Chapter 4. Chapter 5. Chapter 6. Chapter 7. Appendix.     . ‡‡”ƒŽ‹–”‘†— –‹‘ƒ†‘—–Ž‹‡‘ˆ–Š‡–Š‡•‹•   Š‡ ’”‘‹• —‘—• ‡œ›‡ ‡†‹—Ǧ Šƒ‹ ͵Ǧ‡–‘Ǧƒ ›ŽǦ‘ –Š‹‘Žƒ•‡–”‹‰‰‡”•ƒ˜‹ ‹‘—• › Ž‡‹ˆƒ––›Ǧƒ ‹†„‡–ƒǦ‘š‹†ƒ–‹‘   ”ƒ• ”‹’–‘‹  ƒƒŽ›•‹• •—‰‰‡•–• ƒ ‘’‡•ƒ–‘”› ”‘Ž‡ ‘ˆ ‘ˆƒ –‘”• ‘‡œ›‡ƒ†Ϊ‹‡†‹—Ǧ Šƒ‹ƒ ›ŽǦ‘ †‡Š›†”‘‰‡ƒ•‡‘ ‘—–‹ ‡   Š‡ ”‘Ž‡ ‘ˆ Š‡’ƒ–‹  ˆƒ––›Ǧƒ ‹† ‘š‹†ƒ–‹‘ †—”‹‰ ‘Ž† •–”‡••ǣ ”‡‘†‡Ž‹‰‘ˆŠ‡’ƒ–‹ ‡–ƒ„‘Ž‹•‹ƒ‘—•‡™‹–Š‡†‹—Ǧ Šƒ‹ƒ ›ŽǦ‘†‡Š›†”‘‰‡ƒ•‡†‡ˆ‹ ‹‡ ›   ‹—Žƒ–‹‰ –Š‡ ‹’ƒ – ‘ˆ ‰‡‡–‹  ƒ† ‡˜‹”‘‡–ƒŽ ‘†‹ˆ‹‡”• ‘  †‡ˆ‹ ‹‡ › ‹ ƒ ‡š–‡†‡† ‘†‡Ž ‘ˆ Š—ƒŽ‹˜‡”ˆƒ––›Ǧƒ ‹† ƒ–ƒ„‘Ž‹•   ‘™ƒ”†• ‹†‡–‹ˆ›‹‰ in vitro ‡–ƒ„‘Ž‹  ƒ†ƒ’–ƒ–‹‘• –Šƒ– ‡š’Žƒ‹•›’–‘ƒ–‘Ž‘‰›‹‹†‹˜‹†—ƒŽ•Ǥ •Š‘”–”‡’‘”–  . ‡‡”ƒŽ†‹• —••‹‘     —ƒ”›  ƒ‡˜ƒ––‹‰   ‘™Ž‡†‰‡‡–•  ‹‘‰”ƒ’Š›  ‘”–ˆ‘Ž‹‘  ‹•–‘ˆ’—„Ž‹ ƒ–‹‘• . 9. 39. 67. 127. 157. 205. 225. 241 243 249 255 265 269 273.

(18)

(19) Chapter 1 General introduction and outline of the thesis   .    . .

(20)

(21) General introduction and outline of the thesis. Introduction Š‡ƒƒŽ‹ƒ„‘†›†‡’‡†•‘ƒ™‹†‡”ƒ‰‡‘ˆ ‡ŽŽ—Žƒ”ƒ†•›•–‡‹ ’”‘ ‡••‡•Ǥ•—„•‡– ‘ˆ –Š‡•‡ ’”‘ ‡••‡• ƒ”‡ ’Š›•‹ ‘ Š‡‹ ƒŽ ’”‘ ‡••‡• ƒ† „‹‘ Š‡‹ ƒŽ ”‡ƒ –‹‘• –Šƒ– ƒ”‡ ƒ–ƒŽ›œ‡† „› ‡œ›‡• ƒ† –”ƒ•’‘”–‡”•Ǥ Š‡•‡ ’”‘ ‡••‡• ƒ† ”‡ƒ –‹‘• ˆƒŽŽ ™‹–Š‹ –Š‡ ƒ–‡‰‘”›‘ˆ‡–ƒ„‘Ž‹•Ǥ‰‘‹‰”‡•‡ƒ” Š‹ƒƒŽ‹ƒ‡–ƒ„‘Ž‹•ƒ†‡–ƒ„‘Ž‹ †‹•‡ƒ•‡ Šƒ• ‰‡‡”ƒ–‡† ƒŒ‘” ƒ†˜ƒ ‡• ‹ –Š‡ Žƒ•– †‡ ƒ†‡•Ǥ Š‹• ‹• “—‹–‡ ‹’‘”–ƒ–ǡ ƒ• ƒ “—‹”‡† ‡–ƒ„‘Ž‹  †‹•‡ƒ•‡ Šƒ• „‡ ‘‡ ƒ ™‘”Ž†™‹†‡ ‡’‹†‡‹  †—‡ –‘ ƒ —Š‡ƒŽ–Š› Ž‹ˆ‡•–›Ž‡ ƒ† ƒ ƒ‰‹‰’‘’—Žƒ–‹‘ȏͳȂͶȐǤ‘”‡‘˜‡”ǡƒ›‘”‡‹„‘”‡–ƒ„‘Ž‹ ‡””‘”•ƒ”‡„‡‹‰†‹• ‘˜‡”‡† †—‡–‘‡ƒ”Ž›• ”‡‡‹‰‡ˆˆ‘”–•ȏͷȂͳ͵ȐǤ†‡”•–ƒ†‹‰‡–ƒ„‘Ž‹•ƒ†‡–ƒ„‘Ž‹ †‹•‡ƒ•‡™‹ŽŽ ‹’”‘˜‡–Š‡ Šƒ ‡•ˆ‘”‡ˆˆ‡ –‹˜‡–”‡ƒ–‡–ƒ†–Š‡Ž‘™‡”‹‰‘ˆ‡˜‡””‹•‹‰Š‡ƒŽ–Š ƒ”‡ ‘•–•Ǥ Š‡ƒŒ‘”“—‡•–‹‘‹–Š‡ˆ‹‡Ž†‹•™Šƒ–ƒ”‡–Š‡‘Ž‡ —Žƒ”‡ Šƒ‹••—†‡”Ž›‹‰‡–ƒ„‘Ž‹  †‹•‡ƒ•‡ȏ͵ǡͳͶȂͳ͹ȐǤ. Common acquired metabolic diseases  “—‹”‡† ‡–ƒ„‘Ž‹  †‹•‡ƒ•‡• ƒ”‡ ‘Ǧ ‘—‹ ƒ„Ž‡ǡ —Ž–‹ˆƒ –‘”‹ƒŽ †‹•‡ƒ•‡• –Šƒ– ƒ› ’”‘‰”‡••‘˜‡”–‹‡ȏͳͺȐǤŠ‡›ƒ”‡‘‡‘ˆ–Š‡‘•– ‘‘‘Ǧ ‘—‹ ƒ„Ž‡†‹•‡ƒ•‡‰”‘—’• ƒˆˆ‡ –‹‰ ‰Ž‘„ƒŽ Š‡ƒŽ–ŠǤ  ‘”†‹‰ –‘ –Š‡ ‘”Ž† ‡ƒŽ–Š ”‰ƒ‹œƒ–‹‘ǡ –Š‡ ’”‡˜ƒŽ‡ ‡ ‘ˆ ‘˜‡”™‡‹‰Š–ƒ†‘„‡•‹–›Šƒ•–”‹’Ž‡†•‹ ‡ͳͻ͹ͷȏͳͻȐǤƒ”–‹ —Žƒ”Ž›‘„‡•‹–›ǡƒˆˆŽ‹ –‹‰‘”‡–Šƒ ͳͻΨ‘ˆ–Š‡‡•–‡”’‘’—Žƒ–‹‘ȋͳʹǤͷΨ‹–Š‡‡–Š‡”Žƒ†•ƒ†͵ͺΨ‹–Š‡ȌȏʹͲȐǡ‹ ”‡ƒ•‡• –Š‡”‹•‘ˆ‡–ƒ„‘Ž‹ †‹•‡ƒ•‡•ǡ‹ Ž—†‹‰–›’‡ʹ†‹ƒ„‡–‡•‡ŽŽ‹–—•ȋʹȌǡƒ†‘ƒŽ ‘Š‘Ž‹  ˆƒ––›Ž‹˜‡”†‹•‡ƒ•‡ȋ ȌȏͳȂͶȐǤʹˆ‘”‡šƒ’Ž‡ǡ‹• Šƒ”ƒ –‡”‹œ‡†„›‹•—Ž‹”‡•‹•–ƒ ‡‘ˆ ’‡”‹’Š‡”ƒŽ –‹••—‡• ƒ† ‹’ƒ‹”‡† ‹•—Ž‹ •‡ ”‡–‹‘ „› –Š‡ ’ƒ ”‡ƒ• —’‘ ‹ ”‡ƒ•‡† „Ž‘‘† ‰Ž— ‘•‡ Ž‡˜‡Ž• ȏʹͳǡʹʹȐǤ Š‡ ”‡•—Ž–‹‰ Š‹‰Š „Ž‘‘† ‰Ž— ‘•‡ Ž‡˜‡Ž• ȋŠ›’‡”‰Ž› ‡‹ƒȌ †ƒƒ‰‡ ’ƒ ”‡ƒ–‹  ‡ŽŽ•ǡ Ǧ ‡ŽŽ•ǡ ‡”˜‡•ǡ ƒ† „Ž‘‘† ˜‡••‡Ž•ǡ ƒ† ‘•‡“—‡–Ž› ƒ—•‡ ƒŒ‘” Š‡ƒŽ–Š ’”‘„Ž‡• ‹ Ž—†‹‰ ƒ”†‹‘˜ƒ• —Žƒ” †‹•‡ƒ•‡•ǡ •–”‘‡ǡ „Ž‹†‡••ǡ ‡—”‘†‡‰‡‡”ƒ–‹˜‡ †‹•‡ƒ•‡ǡ ƒ† ƒ ‡” ȏʹͳǡʹ͵ȂʹͷȐǤ ‘ƒŽ ‘Š‘Ž‹  ˆƒ––› Ž‹˜‡” †‹•‡ƒ•‡ ȋ Ȍ Šƒ• ƒ ’”‡˜ƒŽ‡ ‡ ‘ˆ ‘˜‡” ʹͲΨǡƒ‹‰‹––Š‡‘•– ‘‘ ‹‡•–‡” ‘—–”‹‡•ȏʹ͸ȂʹͻȐǤŠ‡†‹•‡ƒ•‡ ƒ’”‘‰”‡•• ˆ”‘•‹’Ž‡Ž‹’‹†ƒ ——Žƒ–‹‘ȋ•–‡ƒ–‘•‹•Ȍ–‘‘ƒŽ ‘Š‘Ž‹ •–‡ƒ–‘Š‡’ƒ–‹–‹•ȋi.e.‹ˆŽƒƒ–‹‘ ‘ˆ–Š‡Ž‹˜‡”™‹–Š ‘ —””‡–ˆƒ–ƒ ——Žƒ–‹‘‹Ž‹˜‡”Ȍ–‘ ‹””Š‘•‹•–‘Š‡’ƒ–‘ ‡ŽŽ—Žƒ” ƒ” ‹‘ƒ ȏ͵ͲȂ͵͵ȐǤ‘‘ Šƒ”ƒ –‡”‹•–‹ •‹–Š‡•‡†‹•‡ƒ•‡•‹ Ž—†‡‡š ‡••‹˜‡‰Ž— ‘•‡ƒ†ˆƒ––›Ǧƒ ‹† •—’’Ž› –‘ –Š‡ Ž‹˜‡”ǡ ”‡•—Ž–‹‰ ‹ ‹ˆŽƒƒ–‹‘ƒ†‘š‹†ƒ–‹˜‡ •–”‡•• ȏ͵ͶȂ͵͸ȐǤ ȾǦ ‡ŽŽ•–Šƒ– ƒ”‡ Š”‘‹ ƒŽŽ›‡š’‘•‡†–‘Š‹‰Š‰Ž— ‘•‡ƒ†ˆ”‡‡ˆƒ––›ƒ ‹†Ž‡˜‡Ž•ǡ•Š‘™Š‹‰Š‡””‡ƒ –‹˜‡‘š›‰‡ •’‡ ‹‡•ȋȌ’”‘†— –‹‘Ǥ‹–—””‡†— ‡•‹•—Ž‹‰‡‡‡š’”‡••‹‘ƒ†‹•—Ž‹ ‘–‡–ǡ ƒ† ƒ –‹˜ƒ–‡• — ‘—’Ž‹‰ ’”‘–‡‹ ʹ ȋʹȌǤ Š‡ Žƒ––‡” Ž‘™‡”• ’”‘†— –‹‘ ƒ† ‹Š‹„‹–• ‰Ž— ‘•‡Ǧ•–‹—Žƒ–‡†‹•—Ž‹•‡ ”‡–‹‘ȏ͵͹ȐǤ˜‡”‡š’”‡••‹‘‘ˆƒ–‹‘š‹†ƒ–‡œ›‡•Šƒ•„‡‡ ”‡’‘”–‡†–‘’”‘–‡ –ȾǦ ‡ŽŽ•ˆ”‘†›•ˆ— –‹‘ȏ͵͹ȐǤƒŽ•‘‹†— ‡•‹•—Ž‹”‡•‹•–ƒ ‡‘ˆ–ƒ”‰‡– –‹••—‡•„›‹Š‹„‹–‹‰‹•—Ž‹•‹‰ƒŽ–”ƒ•†— –‹‘ȏ͵ͺǡ͵ͻȐǤ ‘”†‹‰Ž›ǡŠ‹‰ŠǦˆƒ–Ǧ‹†— ‡†‹•—Ž‹ ”‡•‹•–ƒ ‡ Šƒ• „‡‡ ’”‡˜‡–‡† „› ”‡†— ‹‰  –Š”‘—‰Š ƒ–‹‘š‹†ƒ– –”‡ƒ–‡– ‘” ‘˜‡”‡š’”‡••‹‘‘ˆƒ–‹‘š‹†ƒ–‡œ›‡•ȏ͵͹ȐǤš‹†ƒ–‹˜‡•–”‡••ƒŽ•‘’Žƒ›•ƒ‹’‘”–ƒ–”‘Ž‡‹ Ž‹˜‡”†‹•‡ƒ•‡’”‘‰”‡••‹‘ȏͶͲȐǤŠ‹•‹•–‘„‡‡š’‡ –‡†ǡƒ•–Š‡Ž‹˜‡”Šƒ”„‘”•ƒŽ‘–‘ˆ’”‘ ‡••‡•‹ ™Š‹ Š  ‹• ‰‡‡”ƒ–‡†ǡ ‹ Ž—†‹‰ ’”‘–‡‹ •›–Š‡•‹• ȏͶͲȐǡ ‹–‘ Š‘†”‹ƒŽ ”‡•’‹”ƒ–‹‘ ƒ† †‡–‘š‹ˆ‹ ƒ–‹‘ȏͶͲȐǤš ‡••‹˜‡•—’’Ž›‘ˆˆƒ––›ƒ ‹†•‹‘„‡•‹–›™‘—Ž†‘˜‡”™Š‡Ž–Š‡‡Ž‡ –”‘ –”ƒ•’‘”– Šƒ‹ǡ Ž‡ƒ†‹‰ –‘ ‡š ‡••‹˜‡  ’”‘†— –‹‘ ƒ† ‹–‘ Š‘†”‹ƒŽ †›•ˆ— –‹‘Ǥ ‹–‘ Š‘†”‹ƒŽ†›•ˆ— –‹‘™‘—Ž†‹–—”ƒ’Ž‹ˆ›‡š ‡••‹˜‡’”‘†— –‹‘”‡•—Ž–‹‰‹Ž‹’‹† ƒ† ’”‘–‡‹ ’‡”‘š‹†ƒ–‹‘ ƒ† †‡”‡‰—Žƒ–‹‘ ‘ˆ Š‡’ƒ–‹  ‡–ƒ„‘Ž‹• ‹ ‰‡‡”ƒŽǤ

(22)  ƒ††‹–‹‘ǡ ͳͳ. 1.

(23) Chapter 1 ‡š ‡••‹˜‡‹†— ‡•‹ˆŽƒƒ–‘”› ›–‘‹‡•ǡ™Š‹ Š‹–—”‡šƒ ‡”„ƒ–‡’”‘†— –‹‘ƒ† ‹ˆŽƒƒ–‹‘ȏͳͷǡͶͲǡͶͳȐǤ—’’Ž‡‡–ƒ–‹‘‘ˆ–Š‡ƒ–‹‘š‹†ƒ– ˜‹–ƒ‹–‘ ’ƒ–‹‡–•ǡ Šƒ•„‡‡•Š‘™–‘ƒ‡Ž‹‘”ƒ–‡ ƒ–•‡˜‡”ƒŽ•–ƒ‰‡•‘ˆ•‡˜‡”‹–›ȏͳͷȐǤ‰‹‰ƒŽ•‘ƒ‡•ƒ ‹†‹˜‹†—ƒŽ ‘”‡ ’”‘‡ –‘ ‡–ƒ„‘Ž‹  †‹•‡ƒ•‡•ǡ ‹ Ž—†‹‰ Ž‘•• ‘ˆ —• Ž‡ ƒ•• ȋ•ƒ” ‘’‡‹ƒȌǡ ʹǡ ƒ† ƒ”†‹‘˜ƒ• —Žƒ”†‹•‡ƒ•‡ȏͶʹȐǤ

(24) ƒ††‹–‹‘ǡ‘–Š‡”‡–ƒ„‘Ž‹–‡•ƒ”‡ƒŽ•‘‡‡”‰‹‰ƒ•”‡Ž‡˜ƒ– ‘–”‹„—–‘”•‹‡–ƒ„‘Ž‹ †‹•‡ƒ•‡ǡ ‹ Ž—†‹‰•’‡ ‹ˆ‹ –›’‡• ‘ˆŽ‹’‹†•ǡ Ϊǡ ‘‡œ›‡ƒ†ƒ‹‘ƒ ‹†•Ǥ‡Ž‘™ǡ

(25) ™‹ŽŽ†‹• —•• ‡ƒ Š‘ˆ–Š‡•‡ȋ Žƒ••‡•‘ˆȌ‡–ƒ„‘Ž‹–‡•‹‘”‡†‡–ƒ‹ŽǤ . Metabolites and common acquired metabolic disease Lipid regulators ‹’‹†• ƒ”‡ ’”‡†‘‹ƒ–Ž› ‘™ ƒ• ‡†‹ƒ–‘”• ‘ˆ –‘š‹ ‹–› ƒ† ‹ˆŽƒƒ–‹‘ ‹ ‡–ƒ„‘Ž‹  †‹•‡ƒ•‡Ǥ ‡ ‡–Ž› Š‘™‡˜‡”ǡ •–—†‹‡• Šƒ˜‡ ‹†‡–‹ˆ‹‡† Ž‹’‹† Žƒ••‡• –Šƒ– ƒ’’‡ƒ” –‘ ˆ— –‹‘ ‹ •‹‰ƒŽ‹‰ƒ† ƒ‹†— ‡ƒ–‹Ǧ‹ˆŽƒƒ–‘”›‡ Šƒ‹••Ǥ‹’‘‹‡•ǡˆ‘”‹•–ƒ ‡ǡ ƒˆ— –‹‘ ƒ••‘Ž—„Ž‡•‹‰ƒŽ•‘—–•‹†‡–Š‡ ‡ŽŽ•Ǥ‡šƒ’Ž‡‹•ͳ͸ǣͳ͹Ǧ’ƒŽ‹–‘Ž‡ƒ–‡ȏͶ͵ǡͶͶȐǤƒŽ‹–‘Ž‡ƒ–‡ •›–Š‡•‹•‹•‹ ”‡ƒ•‡†ƒ†‹–•„Ž‘‘†Ž‡˜‡Ž•”‹•‡ƒ•ƒ”‡•—Ž–‘ˆ†‡‘˜‘Ž‹’‘‰‡‡•‹•‹ƒ†‹’‘•‡ –‹••—‡ǤŠ‹•Ž‹’‹†‹•ƒ„Ž‡–‘•—’’”‡••‹ˆŽƒƒ–‹‘ƒ†Ž‹˜‡”Ž‹’‘‰‡‡•‹•ƒ†•–‹—Žƒ–‡•‰Ž— ‘•‡ —’–ƒ‡„›•‡Ž‡–ƒŽ—• Ž‡ȏͶ͵ȂͶ͸ȐǤ

(26) ƒ ”‘’Šƒ‰‡•‹–ƒŽŽ‡˜‹ƒ–‡•Ž‹’‘–‘š‹ ‹–›Ǧ‹†— ‡†•–”‡•• ƒ† ‡ŽŽ †‡ƒ–ŠǤ ‘–Š‡” ‡†‘‰‡‘—• Ž‹’‹† Žƒ•• ‘•‹•–• ‘ˆ ˆƒ––›Ǧƒ ‹† Š›†”‘š›Ǧˆƒ––› ƒ ‹†• ȋ  •ȌǤŠ‡•‡  •™‡”‡‹†‡–‹ˆ‹‡†„›Ž‹’‹†‘‹ ƒƒŽ›•‹•‘ˆƒ†‹’‘•‡–‹••—‡ƒ†‹–Š‡ ‹” —Žƒ–‹‘ ‘ˆ ‹ ‡ ™‹–Š ‹ ”‡ƒ•‡† de novo Ž‹’‘‰‡‡•‹•Ǥ  •—„ ƒ–‡‰‘”› ‘ˆ –Š‡•‡  •ǡ ’ƒŽ‹–‹ Ǧƒ ‹†ǦŠ›†”‘š›Ǧ•–‡ƒ”‹ Ǧƒ ‹†• ȋ •Ȍǡ Ž‘™‡” „Ž‘‘† ‰Ž— ‘•‡ǡ ‹’”‘˜‡ ‰Ž— ‘•‡ –‘Ž‡”ƒ ‡ǡ •–‹—Žƒ–‡ ‹•—Ž‹ •‡ ”‡–‹‘ǡ ”‡†— ‡ ƒ†‹’‘•‡ –‹••—‡ ‹ˆŽƒƒ–‹‘ ƒ† ‹’”‘˜‡ ‹•—Ž‹ –‘Ž‡”ƒ ‡ ȏͶ͹ȐǤ ‹ƒŽŽ›ǡ ”‡•‘Ž˜‹• ƒ† ’”‘–‡ –‹•ǡ „‘–Š ‘ˆ ™Š‹ Š ƒ”‡ ’”‘†— ‡† „› ƒ–ƒ„‘Ž‹• ‘ˆ ‘‡‰ƒǦ͵ ˆƒ––›Ǧƒ ‹†•ǡ Šƒ˜‡ „‡‡ ”‡’‘”–‡† –‘ ƒŽŽ‡˜‹ƒ–‡ ‘„‡•‹–›Ǧ‹†— ‡† ‹•—Ž‹ ”‡•‹•–ƒ ‡ƒ†Š‡’ƒ–‹ •–‡ƒ–‘•‹•ȏͶͺȂͷͲȐǤ . NAD+  Ϊ †‘‡• ‘– ‘Ž› ’Žƒ› ƒ ‡–”ƒŽ ”‘Ž‡ ƒ• ƒ ”‡†‘š ‹–‡”‡†‹ƒ–‡ ‹ ‡‡”‰› ƒ† ƒ‹‘ ƒ ‹† ‡–ƒ„‘Ž‹•ǡ „—– ‹– ‹• ƒŽ•‘ ‹˜‘Ž˜‡† ‹ †‡–‘š‹ˆ‹ ƒ–‹‘ǡ ƒŽ ‹— –”ƒ•’‘”–ǡ  ”‡’ƒ‹”ǡ ƒ† ’”‘–‡‹ †‡ƒ ›Žƒ–‹‘ ȏͷͳȂͷ͵ȐǤ

(27) –• ’Š‘•’Š‘”›Žƒ–‡† ˆ‘”ǡ Ϊǡ ‹• ‡••‡–‹ƒŽ ˆ‘” Ž‹’‹† „‹‘•›–Š‡•‹•ȏͷʹȂͷͶȐǤ

(28) ‰‡‡”ƒŽǡƒ‹ ”‡ƒ•‡‹ΪŽ‡˜‡Ž•‹’”‘˜‡•‡–ƒ„‘Ž‹ Š‘‡‘•–ƒ•‹• ƒ†’”‡˜‡–•‘”ƒŽŽ‡˜‹ƒ–‡•‡–ƒ„‘Ž‹ †‹•‡ƒ•‡ǤΪ’Žƒ›•ƒ’”‘–‡ –‹˜‡”‘Ž‡‹ʹǡƒ•ΪǦ ‡†‹ƒ–‡† •‹”–—‹ͳ ȋ

(29) ͳȌ •‹‰ƒŽ‹‰ ‹’”‘˜‡• Ž‹˜‡” ƒ† —• Ž‡ ‹•—Ž‹ •‡•‹–‹˜‹–› ƒ† ‰Ž— ‘•‡Ǧ•–‹—Žƒ–‡†‹•—Ž‹•‡ ”‡–‹‘„›ȾǦ ‡ŽŽ•Ǥ

(30) ͳ•‹‰ƒŽ‹‰ƒŽ•‘’”‘‘–‡•‹–‘ Š‘†”‹ƒŽ „‹‘‰‡‡•‹•Ǥ†‹‹•–”ƒ–‹‘‘ˆΪ’”‡ —”•‘”•Šƒ˜‡•‹‹Žƒ”‡ˆˆ‡ –•ƒ† ƒ‡˜‡ƒ––‡—ƒ–‡ Š‹‰ŠǦˆƒ–Ǧ†‹‡–Ǧ‹†— ‡†‘„‡•‹–›‹‹ ‡ȏͶʹȐǤΪƒ†

(31) ͳ’Žƒ›ƒ’”‘–‡ –‹˜‡‘”ƒ‡Ž‹‘”ƒ–‹‰ ”‘Ž‡ ‹  Ǥ š ‡•• Ž‹’‹† •—’’Ž› ‹ –Š‡ Ž‹˜‡” †‡ ”‡ƒ•‡• Š‡’ƒ–‹  Ϊ Ž‡˜‡Ž•ǡ ™Š‹Ž‡ ‘˜‡”‡š’”‡••‹‘ ‘ˆ 

(32) ͳ ”‡˜‡”•‡• Š‡’ƒ–‹  •–‡ƒ–‘•‹• ƒ† Ϊ ’”‡ —”•‘”• ƒ––‡—ƒ–‡ ‹–‘ Š‘†”‹ƒŽ†›•ˆ— –‹‘‹ˆƒ––›Ž‹˜‡”‘ˆŠ‹‰ŠǦˆƒ–Ǧ†‹‡–Ǧˆ‡†‹ ‡ȏͶʹȐǤΪŠƒ•ƒŽ•‘‰ƒ‹‡† ‘•‹†‡”ƒ„Ž‡ƒ––‡–‹‘†—‡–‘‹–•”‘Ž‡‹ƒ––‡—ƒ–‹‰ƒ‰‹‰Ǧ”‡Žƒ–‡†‡–ƒ„‘Ž‹ †‹•‡ƒ•‡•ǤΪ †‡ ”‡ƒ•‡•†—”‹‰ƒ‰‹‰ƒ•ƒ”‡•—Ž–‘ˆ†ƒƒ‰‡ǡŠ‹‰Š‡”‡š’”‡••‹‘‘ˆ–Š‡ΪǦ†‡‰”ƒ†‹‰ ‡œ›‡͵ͺǡƒ† Š”‘‹ ‹ˆŽƒƒ–‹‘ǤŠ‡Žƒ––‡””‡†— ‡•–Š‡ΪǦ”‡‰‡‡”ƒ–‹‰ ƒ’ƒ ‹–›Ǥ. ͳʹ.

(33) General introduction and outline of the thesis SIRT1‘˜‡”‡š’”‡••‹‘‘”ƒ†‹‹•–”ƒ–‹‘‘ˆΪ’”‡ —”•‘”•Šƒ˜‡„‡‡”‡’‘”–‡†–‘’”‘–‡ – ƒ‰ƒ‹•–ƒ‰‡Ǧ”‡Žƒ–‡††‹ƒ„‡–‡•ǡ ƒ ‡”ǡƒ†‹–‘ Š‘†”‹ƒŽ†›•ˆ— –‹‘ȏͶʹȐǤ . Coenzyme A ‘‡œ›‡Šƒ•ƒŽ•‘‰ƒ‹‡†”‡‡™‡†‹–‡”‡•–‹–Š‡‡–ƒ„‘Ž‹ ˆ‹‡Ž†‹”‡ ‡–›‡ƒ”•ȏͷͷȂ͸ͲȐǤ ‘ƒ –‹˜ƒ–‡•ˆƒ––›ƒ ‹†•ˆ‘”‘š‹†ƒ–‹‘ƒ† Šƒ‹‡Ž‘‰ƒ–‹‘Ǥ

(34) –‹•ƒŽ•‘ƒ‡••‡–‹ƒŽ ‘‡œ›‡ ˆ‘”de novoŽ‹’‹†•›–Š‡•‹•ǡ†‡–‘š‹ˆ‹ ƒ–‹‘‘ˆš‡‘„‹‘–‹ •ǡ–Š‡ › Ž‡ǡƒ†–Š‡ ƒ–ƒ„‘Ž‹•‘ˆ ƒ‹‘ƒ ‹†•Ǥ

(35) –Š‡•‡’ƒ–Š™ƒ›•ǡ‘ ƒ„‡‹˜‘Ž˜‡†ƒ•ˆ”‡‡‘ȋˆ”‘Š‡”‡‘”‡ˆ‡””‡†–‘ƒ• ‘ ǡ„‡ ƒ—•‡‘ˆ‹–• Šƒ”ƒ –‡”‹•–‹ –Š‹‘ŽȋȂ Ȍ‰”‘—’Ȍ‘”ƒ•ƒ–Š‹‘‡•–‡”‹–‡”‡†‹ƒ–‡Ǥ

(36) –™ƒ• ”‡ ‡–Ž› •Š‘™ –Šƒ– ‘ Ž‡˜‡Ž• ƒˆˆ‡ – –Š‡ ’Š‡‘–›’‡ ‘ˆ ‘„‡•‹–› ƒ† ʹǤ ‘” ‡šƒ’Ž‡ǡ †‡Ž‡–‹‘ ‘ˆ –Š‡ ‘ „‹‘•›–Š‡•‹• ‡œ›‡ PANK1 ƒ—•‡• Ž‘™‡” •‡”— ‹•—Ž‹ Ž‡˜‡Ž•ǡ Š‹‰Š‡” ‰Ž— ‘•‡–‘Ž‡”ƒ ‡ƒ†‹•—Ž‹•‡•‹–‹˜‹–›ǡƒ†Ž‘™‡”ˆƒ––›Ǧƒ ‹†‘š‹†ƒ–‹‘”ƒ–‡•‹‹ ‡ ȏͷͷȐǤ Š‡ob/obʹ‘—•‡‘†‡ŽŠƒ•†‡”‡‰—Žƒ–‡†‘‡–ƒ„‘Ž‹•ƒ†ƒ„‘”ƒŽŽ›Š‹‰ŠŽ‹˜‡” ‘ Ž‡˜‡Ž•ǡ ™Š‹ Š ‘‹ ‹†‡• ™‹–Š Š‹‰Š „Ž‘‘† ‰Ž— ‘•‡ ƒ† ‹•—Ž‹ Ž‡˜‡Ž• ȋŠ›’‡”‰Ž› ‡‹ƒȌǡ ‹•—Ž‹”‡•‹•–ƒ ‡ƒ†‹ ”‡ƒ•‡†‰Ž— ‘‡‘‰‡‡•‹• ȏ͸ͳǡ͸ʹȐǤ‡Ž‡–‹‘‘ˆPANK1‹–Š‹•‘—•‡ ‘†‡Žƒ––‡—ƒ–‡†–Š‡†‹ƒ„‡–‹ ’Š‡‘–›’‡™‹–ŠŽ‘™‡”–‘–ƒŽ‘Ž‡˜‡Ž•ǡ”‡†— ‡†‹–‘ Š‘†”‹ƒŽ ȾǦ‘š‹†ƒ–‹‘ ƒ† ‰Ž— ‘‡‘‰‡‡•‹•ǡ ‘”ƒŽ‹œ‡† ‰Ž— ‘•‡ Ž‡˜‡Ž•ǡ ƒ† Ž‘™‡” ‹•—Ž‹ Ž‡˜‡Ž•Ǥ Š‡ ‹ ‡ǡŠ‘™‡˜‡”ǡ”‡ƒ‹‡†‘„‡•‡ǡ‹•—Ž‹”‡•‹•–ƒ–ƒ†Š‡’ƒ–‘•–‡ƒ–‘–‹ ȏͷͷȐǤŠ‹••—‰‰‡•–•–Šƒ– Ž‘™‡”‹‰ –Š‡ ‘ Ž‡˜‡Ž• ƒ† ˆƒ––›Ǧƒ ‹† ‘š‹†ƒ–‹‘ ”ƒ–‡ ƒ› Šƒ˜‡ •‹’Ž› ”‡†— ‡† –Š‡ ‰Ž— ‘‡‘‰‡‡•‹•”ƒ–‡ƒ†–Š‡”‡„›–Š‡‹•—Ž‹’”‘†— –‹‘ǡ™Š‹ Š†‘‡•‘– ‘’Ž‡–‡Ž›”‡•‘Ž˜‡ –Š‡ˆƒ––›Ǧƒ ‹†‡š ‡••‹••—‡•ƒ†‹‰Š–‡˜‡‡šƒ ‡”„ƒ–‡Ž‹’‹†–‘š‹ ‹–›Ǧ”‡Žƒ–‡†’”‘„Ž‡•Ǥ ‘–Š‡” ’Žƒ›‡” ‹ ‘‡œ›‡  ‡–ƒ„‘Ž‹• ‹˜‘Ž˜‡† ‹ ‡–ƒ„‘Ž‹  †‹•‡ƒ•‡ ‹• ƒ‹ ͳǤ

(37) – ƒ–ƒŽ›œ‡• –Š‡ †‡‰”ƒ†ƒ–‹‘ ‘ˆ ’ƒ–‡–Š‡‹‡ǡ ƒ ‹–‡”‡†‹ƒ–‡ ‹ ‘ „‹‘•›–Š‡•‹• ƒ† †‡‰”ƒ†ƒ–‹‘ǡ –‘ ’ƒ–‘–Š‡ƒ–‡ ȋ‹–ƒ‹ ͷȌǡ ƒ ‘‡œ›‡  •›–Š‡•‹• ’”‡ —”•‘” ƒ†  •—„•–”ƒ–‡Ǥ„›’”‘†— –‘ˆ–Š‹•”‡ƒ –‹‘‹• ›•–‡ƒ‹‡ǡƒƒ–‹‘š‹†ƒ–Ǥƒ‹ͳƒ’’‡ƒ”•–‘Šƒ˜‡ „‘–Š‹ˆŽƒƒ–‘”›ƒ† ›–‘’”‘–‡ –‹˜‡‡ˆˆ‡ –•ǡ†‡’‡†‹‰‘–Š‡ ‘†‹–‹‘•ȏ͸͵ȐǤ

(38) ”‡Žƒ–‹‘ –‘ʹǡƒ‹ͳ™ƒ•ƒ„Ž‡–‘’”‘–‡ –’ƒ ”‡ƒ–‹ ‹•Ž‡–„‡–ƒ ‡ŽŽ•ƒ‰ƒ‹•–ˆ”‘•–”‡’–‘œ‘–‘ ‹Ǧ ‹†— ‡††‡ƒ–Šin vitroǡƒ†‹–•†‡Ž‡–‹‘Šƒ•„‡‡ƒ••‘ ‹ƒ–‡†™‹–ŠŠ‹‰Š‡”‹ ‹†‡ ‡‘ˆ†‹ƒ„‡–‡• ƒ†‘”‡•‡˜‡”‡‹ˆŽƒƒ–‘”›‹ˆŽƒƒ–‹‘‘ˆ–Š‡‹•Ž‡–•‘ˆƒ‰‡”Šƒ•ȋ‹•—Ž‹–‹•Ȍ‹–Š‡‘Ǧ ‘„‡•‡†‹ƒ„‡–‹ ȋȌ‘—•‡‘†‡Žȏ͸ͶȐǤ . Amino acids Ž”‡ƒ†› •‡˜‡”ƒŽ †‡ ƒ†‡• ƒ‰‘ǡ ‡Ž‡˜ƒ–‡† •‡”— ƒ‹‘ ƒ ‹† Ž‡˜‡Ž• Šƒ˜‡ „‡‡ ƒ••‘ ‹ƒ–‡† ™‹–Š ‘„‡•‹–›ƒ†‹•—Ž‹”‡•‹•–ƒ ‡ȏ͸ͷȐǤ ‘™‡˜‡”ǡ”‡ ‡–ƒ†˜ƒ ‡•‹‡–ƒ„‘Ž‘‹ •–‡ Š‹“—‡• Šƒ˜‡•’ƒ”‡†”‡‡™‡†‹–‡”‡•–‹–Š‡”‡Žƒ–‹‘„‡–™‡‡ƒ‹‘ƒ ‹†•ƒ†‡–ƒ„‘Ž‹ †‹•‡ƒ•‡Ǥ ƒ”–‹ —Žƒ”Ž›ǡ ‹” —Žƒ–‹‰„”ƒ Š‡†Ǧ Šƒ‹ƒ‹‘ƒ ‹†•ȋ•Ȍǡ‡–Š‹‘‹‡ǡƒ†–Š‡ƒ”‘ƒ–‹  ƒ‹‘ƒ ‹†•’Š‡›ŽƒŽƒ‹‡ƒ†–”›’–‘’ŠƒŠƒ˜‡„‡‡Ž‹‡†–‘‘„‡•‹–›ƒ†‹•—Ž‹”‡•‹•–ƒ ‡Ǥ ‹ƒŽ‘†‡Ž•ƒ†Š—ƒ•™‹–Š‘„‡•‹–›ƒ†‹•—Ž‹”‡•‹•–ƒ ‡•Š‘™Ž‘™‡”Ž‡˜‡Ž•‘ˆ‡œ›‡• ‹˜‘Ž˜‡†‹ ƒ–ƒ„‘Ž‹•‹™Š‹–‡ƒ†‹’‘•‡–‹••—‡ȋȌƒ†Ž‘™‡”Š‡’ƒ–‹ ƒ –‹˜‹–›‘ˆ–Š‡ •‡ ‘†‡œ›‡‹–Š‡ ƒ–ƒ„‘Ž‹•’ƒ–Š™ƒ›ǡ†‡Š›†”‘‰‡ƒ•‡ ‘’Ž‡šȋ ȌǤ

(39)  ƒ††‹–‹‘ǡ ‹– ™ƒ• ”‡’‘”–‡† –Šƒ–  ‘˜‡”Ž‘ƒ† ‹ ”‡ƒ•‡• ƒ ›ŽǦ ƒ”‹–‹‡ ƒ ——Žƒ–‹‘ ‹ ”ƒ– —• Ž‡ ȏͶͶǡ͸͸ȐǤ ‡–Š‹‘‹‡ ”‡•–”‹ –‹‘ ™ƒ• ”‡’‘”–‡† –‘ ”‡†— ‡ ƒ†‹’‘•‹–›ǡ ‹ ”‡ƒ•‡ ‹•—Ž‹ •‡•‹–‹˜‹–›ƒ†ƒ––‡—ƒ–‡Š‡’ƒ–‘•–‡ƒ–‘•‹•‹‹ ‡ȏͶͶȐǤŠ‡›ŽƒŽƒ‹‡ƒ†–”›’–‘’Šƒƒ’’‡ƒ” –‘„‡’”‡†‹ –‹˜‡ƒ”‡”•ˆ‘”ʹȏͶͶȐǤ  ͳ͵. 1.

(40) Chapter 1. Advances in approaches and methods to study acquired metabolic diseases Bioinformatic approaches Š‡‘–›’‡Ǧ ‘” –”ƒ‹–Ǧ”‡Žƒ–‡† „‹‘‹ˆ‘”ƒ–‹ • ƒ’’”‘ƒ Š‡•ǡ •— Š ƒ• ‰‡‘‡Ǧ™‹†‡ ƒ••‘ ‹ƒ–‡† •–—†‹‡• ȋ Ȍǡ ƒ”‡ ‘ˆ–‡ —•‡† –‘ †‹• ‘˜‡” ‡ Šƒ‹•• —†‡”Ž›‹‰ ƒ “—‹”‡† ‡–ƒ„‘Ž‹  †‹•‡ƒ•‡ȏ͸͹ȐǤ‹–Š‡˜‡”Ǧ‰”‘™‹‰•ƒ’Ž‡•‹œ‡•‹’‘’—Žƒ–‹‘•–—†‹‡•ƒ†™‹–Š–Š‡†‡˜‡Ž‘’‡– ‘ˆˆƒ•–‡”ƒ†‘”‡†‡–ƒ‹Ž‡†•‡“—‡ ‹‰–‡ Š‹“—‡•ǡ‘”‡‰‡‡Ǧ–”ƒ‹–ƒ••‘ ‹ƒ–‹‘•Šƒ˜‡„‡‡ ˆ‘—†ǤŠ‡•‡ƒ••‘ ‹ƒ–‹‘•ǡŠ‘™‡˜‡”ǡ†‘‘–‡ ‡••ƒ”‹Ž›‹’Ž›„‹‘Ž‘‰‹ ƒŽˆ— –‹‘‘” ƒ—•ƒŽ‹–›Ǥ ††‹–‹‘ƒŽ‡š’‡”‹‡–•ƒ†‡–Š‘†•™‘—Ž†„‡”‡“—‹”‡†–‘—”ƒ˜‡Ž‡ Šƒ‹••—†‡”Ž›‹‰ –Š‡‹˜‡•–‹‰ƒ–‡†–”ƒ‹–•ȏ͸͹ȐǤ‡ ‡–ƒ†˜ƒ ‡•Šƒ˜‡„‡‡ƒ†‡‹–Š‡—•‡‘ˆƒ††‹–‹‘ƒŽDzǦ‘‹ •dz †ƒ–ƒ ‹ Ǥ —”–Š‡”‘”‡ǡ •‘Ǧ ƒŽŽ‡† Dz’ƒ–Š™ƒ› ƒƒŽ›•‹•dz ƒŽŽ‘™• „‹‘Ž‘‰‹ ƒŽ ‹–‡”’”‡–ƒ–‹‘ „ƒ•‡† ‘ „‹‘Ž‘‰‹ ƒŽ ’ƒ–Š™ƒ›Ǧ ǡ ‡–™‘”•Ǧǡ ƒ† ‰‡‡ ‘–‘Ž‘‰‹‡• ȋ •Ȍ ƒ†Ȁ‘” †‹•‡ƒ•‡ „‹‘ƒ”‡”‰‡‡•‡–•ȏ͸ͺȐǤ . Experimental models ™‹†‡”ƒ‰‡‘ˆ‡š’‡”‹‡–ƒŽ‘†‡Ž•Šƒ˜‡„‡‡†‡˜‡Ž‘’‡†‘˜‡”–Š‡›‡ƒ”•–‘•–—†›ƒ “—‹”‡† ‡–ƒ„‘Ž‹ †‹•‡ƒ•‡•Ǥ‘•–™‹†‡Ž›—•‡†ƒ”‡‘—•‡‘†‡Ž•ƒ†in vitro ‡ŽŽ —Ž–—”‡‘†‡Ž•Ǥ ‘” ‡šƒ’Ž‡ǡ†‹‡–ƒ”›ǡ Š‡‹ ƒŽƒ†‰‡‡–‹ ‘—•‡‘†‡Ž•Šƒ˜‡„‡‡†‡˜‡Ž‘’‡†ˆ‘”„‘–Šʹ ƒ†   ȏͳͶǡ͸ͻǡ͹ͲȐǤ ‡–ƒ„‘Ž‹  †‹•‡ƒ•‡ ‘”‹‰‹ƒ–‡• ˆ”‘ ƒ ‘’Ž‡š ‹–‡”’Žƒ› „‡–™‡‡ †‹ˆˆ‡”‡– ‘”‰ƒ‡ŽŽ‡•ǡ ‡ŽŽ• ƒ† –‹••—‡• ‘ˆ ƒ ‘”‰ƒ‹•ǡ ™Š‹ Š ‘ˆ–‡ †‡˜‡Ž‘’• ‘˜‡” –‹‡ –‘ ƒ ’ƒ–Š‘Ž‘‰‹ ƒŽ’”‡•‡–ƒ–‹‘ǤŠ‡”‡ˆ‘”‡ǡ•–—†›‹‰–Š‡™Š‘Ž‡‘—•‡ƒ•‘’’‘•‡†–‘‹†‹˜‹†—ƒŽ ‡ŽŽ• ‘” „‘†› ˆŽ—‹†•ǡ ƒ› ‘ˆˆ‡” ‹•‹‰Š– ‹–‘ ‡ Šƒ‹•• —†‡”Ž›‹‰ ‡–ƒ„‘Ž‹  †‹•‡ƒ•‡ –Šƒ– ƒ”‡ —””‡–Ž›—ƒ––ƒ‹ƒ„Ž‡‹Š—ƒ•Ǥ ‘™‡˜‡”ǡ‘—•‡‘†‡Ž•‹‰Š–‘–„‡ˆ—ŽŽ›–”ƒ•Žƒ–ƒ„Ž‡–‘ Š—ƒ• ȏͳͶǡ͸ͻȐǤ ‘” ‡šƒ’Ž‡ǡ •‡˜‡”ƒŽ   ‘—•‡ ‘†‡Ž• •Š‘™‡† ‰‡‡ ‡š’”‡••‹‘ ’ƒ––‡”•–Šƒ–™‡”‡•‘†‹ˆˆ‡”‡–ˆ”‘–Š‘•‡‘ˆŠ—ƒ•’ƒ–‹‡–•–Šƒ–‘ ‘ Ž—•‹‘•”‡‰ƒ”†‹‰ †‹•‡ƒ•‡•–ƒ‰‡ ‘—Ž†„‡–”ƒ•Žƒ–‡†ˆ”‘‹ ‡–‘Š—ƒ•ȏ͹ͳȐǤ‘”‡”‡ ‡–Ž›ǡŠ—ƒin vitro ƒ† ex vivo ‡ŽŽ ‘” –‹••—‡ ‘†‡Ž•ǡ ™Š‡”‡ ƒ”‡ ‹• –ƒ‡ –‘ —’Š‘Ž† –Š‡ †‹ˆˆ‡”‡–‹ƒ–‡† ‘”‰ƒ ˆ— –‹‘ǡ Šƒ˜‡ ƒŽ•‘ „‡‡ —•‡† –‘ •–—†› ƒ “—‹”‡† ‡–ƒ„‘Ž‹  †‹•‡ƒ•‡ ȏ͸ͻǡ͹ʹȐǤ Š‡•‡ ‹ Ž—†‡ –‹••—‡ •Ž‹ ‡•ǡ —Ž–—”‡† ’”‹ƒ”› Š—ƒ ‡ŽŽ•ǡ ‘Ǧ —Ž–—”‡ ‘ˆ †‹ˆˆ‡”‡– ‡ŽŽ –›’‡• ‘ˆ ƒ •’‡ ‹ˆ‹  –‹••—‡ǡ’ƒ–‹‡–Ǧ†‡”‹˜‡†Š—ƒ’Ž—”‹’‘–‡–•–‡ ‡ŽŽ•ȋŠ•Ȍƒ†‰‡‘‡Ǧ‡†‹–‡†Š—ƒ ‡ŽŽ• ȏ͸ͻǡ͹ʹȂ͹͸ȐǤ . Analytical methods and data analysis

(41) –Š‡’ƒ•–†‡ ƒ†‡•ǡƒŽ•‘ƒŒ‘”ƒ†˜ƒ ‡•™‡”‡ƒ†‡‹–Š‡ƒƒŽ›–‹ ƒŽˆ‹‡Ž†ǤŠ‹•Šƒ•‡ƒ„Ž‡† Dz—Ž–‹Ǧ‘‹ •dz ”‡•‡ƒ” Šǡ ™Š‹ Š ‡ ‘’ƒ••‡• Žƒ”‰‡Ǧ• ƒŽ‡ ƒƒŽ›•‹• ‘ˆ †‹ˆˆ‡”‡– Ž‡˜‡Ž• ‘ˆ ”‡‰—Žƒ–‹‘ ȏͳͶǡʹͳǡ͸ͻǡ͹͹ȂͺͲȐǤ ‘–ƒ„Ž›ǡ  •‡“—‡ ‹‰ ƒ† ƒ•• •’‡ –”‘‡–”› ȋȌ –‡ Š‹“—‡•—•‡†ˆ‘”’”‘–‡‘‹ •ǡŽ‹’‹†‘‹ •ƒ†‡–ƒ„‘Ž‘‹ •Šƒ˜‡‡ƒ„Ž‡†Š‹‰ŠǦ–Š”‘—‰Š’—–ǡ “—ƒ–‹–ƒ–‹˜‡ †‡–‡”‹ƒ–‹‘ ‘ˆ ‰‡‡ ‡š’”‡••‹‘ ƒ† ’”‘–‡‹ǡ •ƒŽŽ ‡–ƒ„‘Ž‹–‡ ƒ† Ž‹’‹† ‘ ‡–”ƒ–‹‘• ȏͷǡ͸ǡ͹͹Ȃͺ͵ȐǤ ‘•‹†‡”‹‰ –Š‡ Žƒ”‰‡ †ƒ–ƒ•‡–• ‰‡‡”ƒ–‡† „› –Š‡•‡ –‡ Š‹“—‡•ǡ ‡–Š‘†•™‡”‡ƒŽ•‘†‡˜‡Ž‘’‡†–‘‹–‡”’”‡––Š‡†ƒ–ƒƒ†–”ƒ•Žƒ–‡–Š‡–‘„‹‘Ž‘‰‹ ƒŽˆ— –‹‘Ǥ ‡šƒ’Ž‡ˆ‘”–Š‡‹–‡”’”‡–ƒ–‹‘‘ˆ•‡“—‡ ‹‰”‡•—Ž–•‹•‰‡‡Ǧ•‡–Ǧ‡”‹ Š‡–ƒƒŽ›•‹• ȋ ȌȏͺͶȐǤ ‡”‡‹ǡ–Š‡‡š’”‡••‹‘‘ˆ‰‡‡•‹•‡˜ƒŽ—ƒ–‡†ƒ––Š‡Ž‡˜‡Ž‘ˆˆ— –‹‘ƒŽŽ›”‡Ž‡˜ƒ– sets‘ˆ‰‡‡•ǤŠ‡•‡•‡–• ‘–ƒ‹‰‡‡•–Šƒ–Šƒ˜‡ƒ„‹‘Ž‘‰‹ ƒŽˆ— –‹‘ǡ Š”‘‘•‘ƒŽŽ‘ ƒ–‹‘ ‘” ƒ••‘ ‹ƒ–‡† ’Š‡‘–›’‡• ‹ ‘‘Ǥ › ‡˜ƒŽ—ƒ–‹‰ ‰‡‡ •‡–•ǡ „‹‘Ž‘‰‹ ƒŽ ˆ— –‹‘• ƒ „‡ ‘”‡‡ƒ•‹Ž›Ž‹‡†–‘‘Ž‡ —Žƒ”‡ Šƒ‹••Ǥ–Š‡”‘ˆ–‡—•‡†’ƒ––‡””‡ ‘‰‹–‹‘–‡ Š‹“—‡•. ͳͶ.

(42) General introduction and outline of the thesis ƒ”‡ ”‹ ‹’Ž‡ ‘’‘‡– ƒŽ›•‹• ȋȌǡ Š‹‡”ƒ” Š‹ ƒŽ Ž—•–‡”‹‰ ƒ† Žƒ••‹ˆ‹ ƒ–‹‘Ǥ ‘” ƒŽŽ –Š‡•‡ –›’‡• ‘ˆ †ƒ–ƒ ƒƒŽ›•‹•ǡ ƒ ”ƒ‰‡ ‘ˆ ‰”ƒ’Š‹ ƒŽǦ—•‡”Ǧ‹–‡”’Šƒ•‡ ȋ 

(43) Ȍ ‘Ž‹‡ –‘‘Ž• ƒ† ˆ”‡‡Ž›Ǧ†‘™Ž‘ƒ†ƒ„Ž‡ •‘ˆ–™ƒ”‡ Šƒ• „‡‡ †‡˜‡Ž‘’‡†ǡ „ƒ•‡† ‘ ‘‘ ’”‘‰”ƒ‹‰ Žƒ‰—ƒ‰‡•ǡ •— Š ƒ• Ǥ Š‹• ƒ‡• ’”‘ ‡••‹‰ ƒ† ‹–‡”’”‡–ƒ–‹‘ ‘ˆ ‘‹ • †ƒ–ƒ ‘”‡ ‡ƒ•‹Ž› ƒ ‡••‹„Ž‡ƒ†—•‡”Ǧˆ”‹‡†Ž›Ǥ‘’—Žƒ”•‘ˆ–™ƒ”‡ƒ†‘Ž‹‡–‘‘Ž•‹ Ž—†‡–Š‡Œƒ˜ƒǦ„ƒ•‡†  †‡•–‘’ •‘ˆ–™ƒ”‡ Ǧǡ ƒ† –Š‡ Ǧ„ƒ•‡† Ž—•–˜‹• ƒ† ‡–ƒ„‘ƒƒŽ›•– ȏͺͶȂͺ͹ȐǤ ‹ƒŽŽ›ǡ ‘’”‡Š‡•‹˜‡‘‹ •†ƒ–ƒ„ƒ•‡•ƒ”‡ƒ ”— ‹ƒŽƒ‹†‹‹–‡”’”‡–‹‰˜ƒ•–ƒ‘—–•‘ˆ‰‡‡”ƒ–‡† †ƒ–ƒǤ‡š––‘–Š‡™‹†‡Ž›‘™†ƒ–ƒ„ƒ•‡••— Šƒ•. ȏͺͺȐǡ ‡ƒȏͺͻȐǡ—„ Š‡ȏͻͲȐ ƒ† ‹’”‘– ȏͻͳȐǡ –™‘ Š—ƒǦ•’‡ ‹ˆ‹  †ƒ–ƒ„ƒ•‡•ǡ –Š‡ Dz —ƒ ”‘–‡‹ –Žƒ•dz ȏͻʹȐ ƒ† –Š‡ Dz —ƒ‡–ƒ„‘Ž‘‡ƒ–ƒ„ƒ•‡dzȋ Ȍȏͻ͵ǡͻͶȐƒ”‡”‡Ž‡˜ƒ–ˆ‘”–Š‡‡–ƒ„‘Ž‹ †‹•‡ƒ•‡ˆ‹‡Ž†Ǥ Š‡Dz —ƒ”‘–‡‹–Žƒ•dz‹•ƒ‡ƒ•›–‘—•‡‡„Ǧ„ƒ•‡††ƒ–ƒ„ƒ•‡–Šƒ–’”‘˜‹†‡•ƒ ‘„‹ƒ–‹‘ ‘ˆ “—ƒ–‹–ƒ–‹˜‡  ‡š’”‡••‹‘Ǧ ƒ† ‹—‘Š‹•–‘ Š‡‹•–”›Ǧ„ƒ•‡† ”‡Žƒ–‹˜‡ ’”‘–‡‹ ‘ ‡–”ƒ–‹‘†ƒ–ƒˆ‘”͵ʹ†‹ˆˆ‡”‡–Š—ƒ–‹••—‡•ƒ†‘”‰ƒ•ǡ ‘˜‡”‹‰εͻͲΨ‘ˆ–Š‡’—–ƒ–‹˜‡ ’”‘–‡‹Ǧ ‘†‹‰‰‡‡•ȏͻʹȐǤ ‹•–Š‡Žƒ”‰‡•–ƒ†‘•– ‘’”‡Š‡•‹˜‡™‡„Ǧ„ƒ•‡†Š—ƒ ‡–ƒ„‘Ž‘‹  †ƒ–ƒ„ƒ•‡Ǥ

(44) – ‘–ƒ‹• ‹ˆ‘”ƒ–‹‘ ƒ„‘—– Š—ƒ ‡–ƒ„‘Ž‹–‡•ǡ ”‡ƒ –‹‘•ǡ ƒ† ‡œ›‡•ǡ™‹–ŠŽ‹•–‘‡–ƒ„‘Ž‹ ’ƒ–Š™ƒ›•ǡ”‡ˆ‡”‡ ‡ƒ†’ƒ–Š‘Ž‘‰‹  ‘ ‡–”ƒ–‹‘•ǡ†‹•‡ƒ•‡ ƒ••‘ ‹ƒ–‹‘•ǡ”‡ˆ‡”‡ ‡•’‡ –”ƒƒ†‘–Š‡””‡Žƒ–‡†‘‹ •†ƒ–ƒ„ƒ•‡•ǤŠ‡•‡–™‘†ƒ–ƒ„ƒ•‡•™‡”‡ •—ˆˆ‹ ‹‡–Ž› ‘’Ž‡–‡ƒ†•–”— –—”‡†–‘‡ƒ„Ž‡–Š‡ ‘•–”— –‹‘‘ˆ ‘’—–ƒ–‹‘ƒŽ‘†‡Ž•‘ˆ ‡–ƒ„‘Ž‹•„ƒ•‡†‘–Š‡•‡†ƒ–ƒ„ƒ•‡•ȏͻͷȂͳͲͲȐǤ . Systems biology and computational modeling ›•–‡• „‹‘Ž‘‰›ǡ ‹ –Š‡ ™‹†‡•– •‡•‡ ‘ˆ –Š‡ ™‘”†ǡ ˆ”‘ ‘””‡Žƒ–‹‘ ƒƒŽ›•‹• –‘ †‡–ƒ‹Ž‡† ‘’—–ƒ–‹‘ƒŽ ‘†‡Ž‹‰ ‘ˆ ‡–ƒ„‘Ž‹  †›ƒ‹ • ‹• ƒ ’‘™‡”ˆ—Ž –‘‘Ž –‘ ‰ƒ‹ ‹•‹‰Š– ‹–‘ ‡–ƒ„‘Ž‹• ƒ† ƒ “—‹”‡† ‡–ƒ„‘Ž‹  †‹•‡ƒ•‡• ȏͳͲͳȂͳͲͶȐǤ ‡‘‡Ǧ• ƒŽ‡ ‡–ƒ„‘Ž‹  ƒ† †›ƒ‹  ‘†‡Ž• ‘ˆ ƒƒŽ‹ƒ ‡–ƒ„‘Ž‹• ƒ”‡ ‰‡––‹‰ ‹ ”‡ƒ•‹‰ ƒ––‡–‹‘ ȏͻͷȂͳͲͲǡͳͲͷȂ ͳͳͲȐǤ ‡‘‡Ǧ• ƒŽ‡ ‡–ƒ„‘Ž‹  ‘†‡Ž• ƒ”‡ •–‘‹ Š‹‘‡–”‹  ‘†‡Ž• –Šƒ– ‘–ƒ‹ ƒŽŽ ‘™ „‹‘ Š‡‹ ƒŽ ƒ†–”ƒ•’‘”– ”‡ƒ –‹‘•‹ –Š‡ ‘†‡Ž‡† ‡–™‘”Ǥ ‘•–”ƒ‹–Ǧ„ƒ•‡†ƒƒŽ›•‹•‘ˆ –Š‡•‡‘†‡Ž•‡ƒ„Ž‡•–Š‡‡•–‹ƒ–‹‘‘ˆ”‡Žƒ–‹˜‡ˆŽ—š†‹•–”‹„—–‹‘•–Š”‘—‰Š–Š‡‡–™‘”ǡ„ƒ•‡† ‘ ƒ •–‡ƒ†›Ǧ•–ƒ–‡ ƒ••—’–‹‘ ƒ† ‘ˆ–‡ ƒŽ•‘ ‘–Š‡” ‘•–”ƒ‹–•ǡ •— Š ƒ• ”‡ƒ –‹‘ –Š‡”‘†›ƒ‹ •ǡ—–”‹‡–•—’’Ž›ǡ‰‡‡‡š’”‡••‹‘ǡ’”‘–‡‹ ‘ ‡–”ƒ–‹‘‘”‘–Š‡”‘‹ •†ƒ–ƒ ȏͳͳͳȐǤ ‘•‡“—‡–Ž›ǡ –Š‡•‡ ‘†‡Ž• ƒ ”‡˜‡ƒŽ ™Š‹ Š ‡ŽŽ—Žƒ” ‡–ƒ„‘Ž‹  ’ƒ–Š™ƒ›• ƒ› ‘–”‹„—–‡ –‘ ƒ ‘„•‡”˜‡† ‡–ƒ„‘Ž‹  •–ƒ–‡ ‘” †‹•‡ƒ•‡Ǥ Š‡› ƒ”‡ ƒŽ•‘ —•‡† –‘ ‹†‡–‹ˆ› „‹‘ƒ”‡”•‘ˆ†‹•‡ƒ•‡Ǥ‡šƒ’Ž‡‹•iHepatocytes2322ǡƒ‰‡‘‡Ǧ• ƒŽ‡‡–ƒ„‘Ž‹ ‘†‡Ž‘ˆ –Š‡Š—ƒŠ‡’ƒ–‘ ›–‡ǡ™Š‹ Š™ƒ•—•‡†–‘‹†‡–‹ˆ›•‡”‹‡†‡ˆ‹ ‹‡ ›‹ ȏͻͻȐǤ—”‰”‘—’ Šƒ•  —”ƒ–‡† –Š‡ Š—ƒ ‡–ƒ„‘Ž‹  ‘†‡Ž ‡ ‘ʹ ȏͻ͸Ȑ –‘ ƒ —”ƒ–‡Ž› ”‡’”‡•‡– –Š‡ ‡–‹”‡ ˆŽƒ˜‘’”‘–‡‘‡ȏͳͳʹȐǤ‡ ‡–Ž›ǡ–Š‡‡–ƒ„‘Ž‹•‘ˆʹͲ‘”‰ƒ•ǡ•‹š•‡š‘”‰ƒ•ǡ•‹š„Ž‘‘† ‡ŽŽ•ǡ –Š‡‰ƒ•–”‘‹–‡•–‹ƒŽŽ—‡ǡ•›•–‡‹ „Ž‘‘† ‹” —Žƒ–‹‘ǡƒ†–Š‡„Ž‘‘†Ǧ„”ƒ‹„ƒ””‹‡”Šƒ˜‡„‡‡ ‘—’Ž‡†‹–‘ƒ•‹‰Ž‡™Š‘Ž‡Ǧ„‘†›‘†‡Žȋ ƒ”˜‡›ƒ† ƒ”˜‡––ƒȌȏͳͳ͵ȐǤ Ž‹‹–ƒ–‹‘‘ˆ•–‘‹ Š‹‘‡–”‹ ‘†‡Ž•‹•–Šƒ––Š‡›Žƒ ‹‡–‹ ‹ˆ‘”ƒ–‹‘Ǥ›ƒ‹ ‡–ƒ„‘Ž‹  ‘†‡Ž•ƒ”‡‘ˆ–‡”‡’”‡•‡–‡†ƒ••›•–‡•‘ˆ‘”†‹ƒ”›†‹ˆˆ‡”‡–‹ƒŽ‡“—ƒ–‹‘•ˆ‘”–Š‡˜ƒ”‹ƒ„Ž‡ ‡–ƒ„‘Ž‹–‡• ‘ˆ –Š‡ ‘†‡Ž‡† ’ƒ–Š™ƒ›•Ǥ Š‡ ‘”†‹ƒ”› †‹ˆˆ‡”‡–‹ƒŽ ‡“—ƒ–‹‘• ‹ Ž—†‡ ƒŽŽ –Š‡ ”‡ƒ –‹‘•ƒ†–”ƒ•’‘”–’”‘ ‡••‡•‹–Š‡‘†‡Ž–Šƒ– ‘•—‡‘”’”‘†— ‡–Š‡‡–ƒ„‘Ž‹–‡‘ˆ ‹–‡”‡•– ƒ– –Š‡ ‘†‡Ž‡† ‹–”ƒ ‡ŽŽ—Žƒ” Ž‘ ƒ–‹‘ ȏͳͳͳǡͳͳͶȐǤ ‡ƒ –‹‘ ƒ† –”ƒ•’‘”– ”ƒ–‡• ƒ”‡ ’”‡ˆ‡”ƒ„Ž›„ƒ•‡†‘†‡–ƒ‹Ž‡†‹‡–‹ ‘™Ž‡†‰‡‘ˆ‡œ›‡Ǧ ƒ–ƒŽ›œ‡†Ǧǡ–”ƒ•’‘”–‡”Ǧ‡†‹ƒ–‡† ƒ†’Š›•‹ ‘ Š‡‹ ƒŽ’”‘ ‡••‡•‹•‹†‡–Š‡ ‡ŽŽȏͳͳͳȐǤ›ƒ‹ ‘†‡Ž•’”‡†‹ –‡–ƒ„‘Ž‹–‡–‹‡ ͳͷ. 1.

(45) Chapter 1 ‘—”•‡•ǡ „—– ƒŽ•‘ •–‡ƒ†› •–ƒ–‡ ‘ ‡–”ƒ–‹‘• ƒ† ˆŽ—š‡•Ǥ Š‡› ‡ƒ„Ž‡ ‡–ƒ„‘Ž‹  ‘–”‘Ž ƒƒŽ›•‹•ǡƒ†•‡•‹–‹˜‹–›ƒƒŽ›•‹•‹‰‡‡”ƒŽǤ‡–ƒ„‘Ž‹  ‘–”‘ŽƒƒŽ›•‹•ȋȌ‹•–Š‡ƒƒŽ›•‹• ‘ˆ –Š‡ •‡•‹–‹˜‹–› ‘ˆ ‘†‡Ž ˜ƒ”‹ƒ„Ž‡•ǡ •— Š ƒ• ˆŽ—š‡• ƒ† ‡–ƒ„‘Ž‹–‡ ‘ ‡–”ƒ–‹‘•ǡ –‘ ‘†—Žƒ–‹‘‘ˆ–Š‡”ƒ–‡‘ˆƒ”‡ƒ –‹‘‘”–”ƒ•’‘”–’”‘ ‡••ǤƒŽŽ‘™•ƒ‰‡‡”ƒŽ‹œ‡†–Š‡‘”‡–‹ ƒŽ ƒƒŽ›•‹•‘ˆ–Š‡”‡Žƒ–‹‘„‡–™‡‡•‡•‹–‹˜‹–› ‘‡ˆˆ‹ ‹‡–•Ǥ‹’‘”–ƒ–‘—– ‘‡‘ˆ‹•–Šƒ– ˆŽ—š ‘–”‘Ž ƒ„‡†‹•–”‹„—–‡†‘˜‡”ƒŽŽ–Š‡•–‡’•‹–Š‡•›•–‡ƒ††‡’‡†•‘–Š‡‡–ƒ„‘Ž‹  •–ƒ–‡‘ˆ–Š‡•›•–‡ȏͳͳͷȂͳͳͺȐǤŠ‹•‹•‹ ‘–”ƒ•––‘–Š‡ Žƒ••‹ ƒŽƒ†‘ˆ–‡‡””‘‡‘—• ‘ ‡’– ‘ˆ‘‡Dz”ƒ–‡ǦŽ‹‹–‹‰dz•–‡’™‹–Šˆ—ŽŽˆŽ—š ‘–”‘ŽǤ

(46) ǡƒŽ•‘–Š‡•‡•‹–‹˜‹–›‘ˆ‘†‡Ž˜ƒ”‹ƒ„Ž‡• –‘‡š–‡”ƒŽ‡ˆˆ‡ –‘”• ƒ„‡ ƒŽ —Žƒ–‡†Ǥš–‡”ƒŽ‡ˆˆ‡ –‘”•ƒ”‡’”‘’‡”–‹‡•‹–Š‡•›•–‡–Šƒ–ƒ”‡ ‘– ‘–”‘ŽŽ‡†„›–Š‡‘†‡Ž‡†•›•–‡ǤŠ‡•‡‹ Ž—†‡ ‘ˆƒ –‘” ‘ ‡–”ƒ–‹‘•–Šƒ–Šƒ˜‡„‡‡ •‡––‘ƒ ‘•–ƒ–˜ƒŽ—‡‘”‡œ›‡ƒˆˆ‹‹–‹‡•ƒ† ƒ–ƒŽ›–‹  ƒ’ƒ ‹–‹‡•–Šƒ–Šƒ˜‡„‡‡•‡– –‘ƒ ‘•–ƒ–˜ƒŽ—‡ȏͳͳͻȐǤŠ‡”‡ Žƒ••‹ ƒŽ‹•ˆ‘ —•‡†‘•–Ž›‘–Š‡ƒƒŽ›•‹•‘ˆ•–‡ƒ†›•–ƒ–‡ǡ –Š‡”‡ƒ”‡ƒ›‡š–‡•‹‘•–Šƒ–†‡ƒŽ™‹–Š†›ƒ‹ •ǡ™Š‹ Šƒ›„‡”‡Ž‡˜ƒ––‘‰ƒ‹‹•‹‰Š–‹–‘ ‡ Šƒ‹•• —†‡”Ž›‹‰ †‹•‡ƒ•‡ ’”‘‰”‡••‹‘ ‘˜‡” –‹‡Ǥ  ‹’‘”–ƒ– ‡š–‡•‹‘ ƒŽŽ‘™• –‘ “—ƒ–‹ˆ›–Š‡ ‘–”‹„—–‹‘‘ˆ‹†‹˜‹†—ƒŽ˜ƒ”‹ƒ„Ž‡”‡‰—Žƒ–‘”••— Šƒ•Ǧ‡†‹ƒ–‡†”‡‰—Žƒ–‹‘ ƒ†‡–ƒ„‘Ž‹–‡•–‘–Š‡ Šƒ‰‡‘ˆ”‡ƒ –‹‘”ƒ–‡•‘˜‡”–‹‡ȏͳʹͲȐǤŠ‹•‹•‹’‘”–ƒ–ǡ•‹ ‡‹– ‰‹˜‡• †‡–ƒ‹Ž‡† ‹•‹‰Š– ‹–‘ –Š‡ ‡–‹‘Ž‘‰› ‘ˆ ƒ ’ƒ–Š‘Ž‘‰‹ ƒŽ ‘†‹–‹‘Ǥ

(47) – ‹• ‹’‘”–ƒ– –‘ ‘–‡ Š‘™‡˜‡”ǡ–Šƒ––Š‡‘—– ‘‡•†‡’‡†‘–Š‡Ž‡˜‡Ž‘ˆ†‡–ƒ‹Žƒ†ƒ —”ƒ ›‘ˆ–Š‡†›ƒ‹ ‘†‡ŽǤ Š‡”‡ˆ‘”‡ǡƒˆ— –‹‘ƒŽ’Š‡‘‡‘†‹• ‘˜‡”‡†in silicoǡ•Š‘—Ž†„‡˜ƒŽ‹†ƒ–‡†in vitro or in vivo ȏͳͳͳȐǤ šƒ’Ž‡•‘ˆ†›ƒ‹ ‘†‡Ž•‘ˆ‡–ƒ„‘Ž‹•ƒ†ƒ “—‹”‡†‡–ƒ„‘Ž‹ †‹•‡ƒ•‡‹ Ž—†‡‘†‡Ž• ‘ˆ Š‡’ƒ–‹  ‰Ž— ‘•‡ ‡–ƒ„‘Ž‹• ™‹–Š Š‘”‘ƒŽ ”‡‰—Žƒ–‹‘ ȏͳʹͳȐǡ ‹–‘ Š‘†”‹ƒŽ ‡‡”‰› ‡–ƒ„‘Ž‹• ȏͳͲ͹ǡͳʹʹȐǡ œ‘ƒ–‹‘ ‘ˆ Š‡’ƒ–‹  ‡‡”‰› ‡–ƒ„‘Ž‹•ǡ ‹•—Ž‹ ”‡•‹•–ƒ ‡ ƒ† •–‡ƒ–‘•‹•ȏͳʹ͵Ȑǡ‰Ž— ‘•‡ƒ†ƒ‹‘ƒ ‹†Ǧ‹†— ‡†‹•—Ž‹•‡ ”‡–‹‘‹ƒ’ƒ ”‡ƒ–‹ ȾǦ ‡ŽŽȏͳʹͶȐǡ ‡–ƒ„‘Ž‹  •›†”‘‡ ƒ† †›•Ž‹’‹†‡‹ƒ ȏͳʹͷȐǡ ƒ†‹–‘ Š‘†”‹ƒŽ ˆƒ––›Ǧƒ ‹†‘š‹†ƒ–‹‘ȏͳͲͺȐǤ Š‡ •‹—Žƒ–‹‘• ‰‡‡”ƒ–‡† ™‹–Š –Š‡•‡ ‘†‡Ž• •—‰‰‡•– –Šƒ– ™‡ ƒ”‡ —””‡–Ž› ƒ„Ž‡ –‘ ‰ƒ‹ ‘•‹†‡”ƒ„Ž‡‹•‹‰Š–‹–‘–Š‡™‘”‹‰•‘ˆ‡–ƒ„‘Ž‹•ƒ†‡–ƒ„‘Ž‹ †‹•‡ƒ•‡ǡ‡•’‡ ‹ƒŽŽ›™Š‡ —•‡†‹ ‘„‹ƒ–‹‘™‹–Š—Ž–‹Ǧ‘‹ •†ƒ–ƒǤ . Inborn errors of metabolism/Inherited metabolic diseases

(48) „‘” ‡””‘”• ‘ˆ ‡–ƒ„‘Ž‹• ȋ

(49) Ȍ ƒ”‡ ‹Š‡”‹–‡† †‹•‡ƒ•‡• ’”‹ƒ”‹Ž› ƒ—•‡† „› ’ƒ–Š‘‰‡‹  —–ƒ–‹‘•‹‰‡‡•–Šƒ– ‘†‡ˆ‘”‡–ƒ„‘Ž‹ ‡œ›‡•‘”–”ƒ•’‘”–’”‘–‡‹•Ǥ

(50) •Šƒ˜‡„‡‡ Žƒ••‹ˆ‹‡†‹–‘ͳȌ‹–‘š‹ ƒ–‹‘†‹•‡ƒ•‡•ǡ‹ Ž—†‹‰ƒ‹‘Ǧƒ ‹†‘’ƒ–Š‹‡•ƒ†‘”‰ƒ‹ ƒ ‹†—”‹ƒ•ǡ ʹȌ‹„‘”‡””‘”•‘ˆ‡‡”‰›‡–ƒ„‘Ž‹•ǡ‹ Ž—†‹‰‹–‘ Š‘†”‹ƒŽ”‡•’‹”ƒ–‘”›Ǧ Šƒ‹ƒ†ˆƒ––›Ǧ ƒ ‹†‘š‹†ƒ–‹‘†‡ˆ‹ ‹‡ ‹‡•ǡƒ†͵Ȍ†‹•‡ƒ•‡•”‡Žƒ–‡†–‘‹’ƒ‹”‡††‡‰”ƒ†ƒ–‹‘‘”•›–Š‡•‹•‘ˆ ‘’Ž‡š ‘Ž‡ —Ž‡•ǡ •— Š ƒ• ‰Ž› ‘‰‡ •–‘”ƒ‰‡ †‹•‡ƒ•‡ ƒ† ‘‰‡‹–ƒŽ †‹•‘”†‡”• ‘ˆ ‰Ž› ‘•›Žƒ–‹‘ ȏͳʹ͸ȐǤ ‘‡ ‘ˆ –Š‡•‡ †‡ˆ‡ –• ˆƒŽŽ ‹–‘ —Ž–‹’Ž‡ Žƒ••‡•Ǥ ‘ŽŽ‡ –‹˜‡Ž›ǡ –Š‡

(51)  ’”‡˜ƒŽ‡ ‡™ƒ•ͳȀʹͶͲͲ‹ ‡”ƒ›ʹͲͲ͵ƒ†ͳȀͳͺͻͶ‹

(52) –ƒŽ›‹ʹͲͳͷȏ͸ǡͻǡͳͲǡͳͺǡͳͲʹǡͳʹ͹ȐǤ ‡‘ˆ–Š‡‘•– ‘‘

(53) •‹•‡†‹—Ǧ Šƒ‹ƒ ›ŽǦ‘†‡Š›†”‘‰‡ƒ•‡ȋȌ†‡ˆ‹ ‹‡ › ȋȌȏͺȂͳͲǡͳͺǡͳͲʹǡͳʹ͹ȐǤŠ‡’”‡˜ƒŽ‡ ‡ƒ–„‹”–Š™ƒ•ͳȀͺ͵ͲͲ‹–Š‡‡–Š‡”Žƒ†• „‡–™‡‡ʹͲͲ͹ƒ†ʹͲͳͷ ȏͳʹͺȐƒ†ͳȀͻͲͻ͵‹

(54) –ƒŽ›‹ʹͲͳͷȏ͸ȐǤ‹•ƒ‡œ›‡‘ˆ–Š‡ ‹–‘ Š‘†”‹ƒŽˆƒ––›Ǧƒ ‹†‘š‹†ƒ–‹‘’ƒ–Š™ƒ›Ǥ•’‡ ‹ƒŽŽ›‡™„‘”•ƒ† Š‹Ž†”‡ ƒ’”‡•‡– ™‹–Š ƒ •‡”‹‘—• ‹ŽŽ‡•• ƒ† †‹•‡ƒ•‡ ”‡Žƒ–‡† –‘

(55) •Ǥ ‘•‡“—‡–Ž›ǡ ‡ƒ”Ž› †‹ƒ‰‘•‹• ƒ† –”‡ƒ–‡–„‡ˆ‘”‡–Š‡‘•‡–‘ˆ•›’–‘•‹•‹’‘”–ƒ––‘’”‡˜‡–•‡˜‡”‡’‡”ƒ‡–†ƒƒ‰‡ ‘”†‡ƒ–ŠȏͳͲǡͳͲʹǡͳʹ͹ȐǤ ͳ͸.

(56) General introduction and outline of the thesis. 1. . Common principles underlying IEMs and acquired metabolic diseases

(57) •ƒ”‡–›’‹ ƒŽŽ›‘‘‰‡‹ ǡ•‹‰Ž‡Ǧ‡œ›‡†‡ˆ‹ ‹‡ ‹‡•Ǥ‡˜‡”–Š‡Ž‡••ǡ

(58) •‘ˆ–‡†‹•’Žƒ›ƒ •’‡ –”—‘ˆ†‹•‡ƒ•‡’Š‡‘–›’‡•ǡ‡˜‡™‹–Š‹ƒ•—„•‡–‘ˆ‹†‹˜‹†—ƒŽ•™‹–Š–Š‡•ƒ‡—–ƒ–‹‘Ǥ Š‡”‡ˆ‘”‡ǡ

(59) •Šƒ˜‡„‡‡˜‹‡™‡†–‘†‹•’Žƒ› ‘’Ž‡š–”ƒ‹–•ǡ‘–—Ž‹‡ ‘‘ƒ “—‹”‡†ǡ —Ž–‹ˆƒ –‘”‹ƒŽ†‹•‡ƒ•‡•ȏͳͺǡͳͲʹǡͳʹͻȐǤ

(60) –Šƒ•„‡‡’”‘’‘•‡†–Šƒ–‘†‹ˆ›‹‰ˆƒ –‘”•ǡ‹ Ž—†‹‰ ‡˜‹”‘‡–ƒŽˆƒ –‘”•ȋ•— Šƒ•†‹‡–ƒ†ƒ„‹‡––‡’‡”ƒ–—”‡ȏͳ͵ͲȐȌǡ‡’‹‰‡‡–‹ ˆƒ –‘”•ƒ† ‘–Š‡”‰‡‡•ǡƒ› ‘–”‹„—–‡–‘–Š‡†‹•‡ƒ•‡’”‡•‡–ƒ–‹‘ȏͳͺȐǤ

(61) ƒ††‹–‹‘ǡ’Š‡‘–›’‡••‹‹Žƒ” –‘ –Š‘•‡ ‘ˆ ƒ “—‹”‡† ‡–ƒ„‘Ž‹  †‹•‡ƒ•‡•ǡ ˆ‘” ‹•–ƒ ‡ Š‡’ƒ–‘•–‡ƒ–‘•‹•ǡ ‘˜‡”™‡‹‰Š– ƒ† †‹ƒ„‡–‡•ǡŠƒ˜‡„‡‡”‡’‘”–‡†‹

(62) •ȏͳͺǡͳ͵ͳǡͳ͵ʹȐǤ

(63) •ƒ›‡˜‡„‡ ‘•‹†‡”‡†ƒ•’ƒ”–‘ˆ –Š‡•ƒ‡‡–ƒ„‘Ž‹ †‹•‡ƒ•‡•’‡ –”—Ǥ–Š‡‘‡‡†‘ˆ–Š‡•’‡ –”—–Š‡†‡ˆ‡ –‹˜‡‰‡‡‘ˆ –Š‡

(64) –‘‰‡–Š‡”™‹–Š‘†‹ˆ›‹‰‰‡‡•ƒ†‘–Š‡”ˆƒ –‘”•†‡–‡”‹‡–Š‡†‹•‡ƒ•‡’”‡•‡–ƒ–‹‘ǡ ‘ˆ–‡ƒ–›‘—‰ƒ‰‡Ǥ–Š‡‘–Š‡”‡†‘ˆ–Š‡•’‡ –”——Ž–‹’Ž‡‰‡‡•–‘‰‡–Š‡”™‹–ŠŽ‹ˆ‡•–›Ž‡ ƒ†Š‹•–‘”›†‡–‡”‹‡–Š‡†‡˜‡Ž‘’‡–‘˜‡”–‹‡‘ˆ ƒ “—‹”‡†‡–ƒ„‘Ž‹ †‹•‡ƒ•‡ȏͳͺȐǤ

(65) –‹• –Š—•‹„‘–Š ƒ•‡•–Š‡ ——Žƒ–‹˜‡‡ˆˆ‡ –‘ˆ†‹ˆˆ‡”‡–‰‡‡˜ƒ”‹ƒ–•’Ž—•‡š–‡”ƒŽˆƒ –‘”•–Šƒ– ”‡•—Ž–‹–Š‡‘„•‡”˜‡†’Š‡‘–›’‡ǤŠ‹•‹•‘–—Ž‹‡–Š‡†‹•–”‹„—–‹‘‘ˆˆŽ—š ‘–”‘Ž‘˜‡”ƒ› ‡œ›‡•‹ƒ‡–ƒ„‘Ž‹ ‡–™‘”Ǥ‘•‡“—‡–Ž›ǡ–Š‡ ‘–”‹„—–‹‘‘ˆƒ‰‡‡–‹ ˜ƒ”‹ƒ–‹‘–‘–Š‡ ’Š‡‘–›’‡†‡–‡”‹‡•™Š‡–Š‡”‹–‹•‹†‡–‹ˆ‹‡†ƒ•ƒ‹„‘”‡””‘”‘”‘–ǤŠ‹•ƒŽ•‘‡ƒ•–Šƒ– Dz™‡ƒ‡” —–ƒ–‹‘•̶ ‹ ƒ ‘–Š‡”™‹•‡ Š‡ƒŽ–Š› ‹†‹˜‹†—ƒŽ ȋ”‡’”‡•‡–‡† „› ƒ ‘„‹ƒ–‹‘ ‘ˆ ‰‡‡–‹ ˜ƒ”‹ƒ–•–Šƒ–”‡•—Ž–‹–Š‡’Š‡‘–›’‡„‡‹‰†‡‘–‡†ƒ•̶Š‡ƒŽ–Š›̶Ȍ™‘—Ž†‘–„‡‡ƒ•‹Ž› †‡–‡ –‡†Ǥ™‡ƒ‡”—–ƒ–‹‘™‘—Ž†„‡ƒ—–ƒ–‹‘–Šƒ–‘‹–•‘™™‘—Ž†‘–”‡•—Ž–‹ƒ Ž‹‹ ƒŽ ’Š‡‘–›’‡Ǥ‡šƒ’Ž‡‹•ƒ •Š‘™‹‰ƒ••‘ ‹ƒ–‹‘‘ˆ•‹‰Ž‡Ǧ— Ž‡‘–‹†‡’‘Ž›‘”’Š‹•• ȋ•Ȍƒ––Š‡Ž‘ —•™‹–Š„Ž‘‘†ͺǦ ƒ”‹–‹‡Ž‡˜‡Ž•ǡƒ„‹‘ƒ”‡”ˆ‘”ȏͳͺǡͳ͵͵ȐǤ ‹ƒŽŽ›ǡ

(66) • ”‡•—Ž– ‹ ƒ ‘”‡ ’ƒ–Š‘Ž‘‰‹ ƒŽ ’Š‡‘–›’‡ ‘’ƒ”‡† –‘ –Š‡ ™‡ƒ‡” —–ƒ–‹‘ ’Š‡‘–›’‡ ȋ•‘‡ •‹‹Žƒ” –‘ ƒ “—‹”‡† ‡–ƒ„‘Ž‹  †‹•‡ƒ•‡Ȍ ƒ† ‹‰Š– –Š‡”‡ˆ‘”‡ „‡ ‘”‡ ˜—Ž‡”ƒ„Ž‡ –‘ ƒ††‹–‹‘ƒŽ ™‡ƒ‡••Ǧ‹ ”‡ƒ•‹‰ ˜ƒ”‹ƒ ‡• ‹ ‘–Š‡” ‰‡‡• ƒ† ‘–Š‡” ˆƒ –‘”•Ǥ Š‡”‡ˆ‘”‡ǡ ‘†‹ˆ›‹‰ ˆƒ –‘”• ȋ‹ Ž—†‹‰ ‰‡‡•Ȍ –Šƒ– ‘–”‹„—–‡ –‘ –Š‡ †‡˜‡Ž‘’‡– ƒ† ’”‘‰”‡••‹‘‘ˆƒ “—‹”‡†‡–ƒ„‘Ž‹ †‹•‡ƒ•‡• ƒ„‡‘”‡‡ƒ•‹Ž›‹†‡–‹ˆ‹‡†™Š‡•–—†›‹‰

(67) •Ǥ ‹‹Žƒ”Ž›ǡ †‹ˆˆ‡”‡ ‡• ‹ ‰‡‡ ‡š’”‡••‹‘ „‡–™‡‡ ‡˜‹”‘‡–ƒŽŽ›Ǧ ŠƒŽŽ‡‰‡†

(68)  ƒ† ‘–”‘Ž‰”‘—’• ‘—Ž†’‘‹––‘ȋƒŽǦȌƒ†ƒ’–ƒ–‹‘•‹‘†‹ˆ‹‡”‰‡‡•Ǥ‹ ‡’ƒ”–‹ —Žƒ”Ž›‡™„‘” ƒ† Š‹Ž†”‡ ™‹–Š

(69) • ƒ ’”‡•‡– ™‹–Š ˜‡”› •‡˜‡”‡ •›’–‘•ǡ ‹– ‹• ˜‡”› ‹’‘”–ƒ– –‘ —†‡”•–ƒ†–Š‡‡–‹‘Ž‘‰›‘ˆ†‹•‡ƒ•‡‹

(70) •Ǥ††‹–‹‘ƒŽŽ›ǡ–Š‡•–—†›‘ˆ

(71) •ƒ›‰‹˜‡‹•‹‰Š–• ‹ ‡ Šƒ‹•• –Šƒ– ƒ”‡ ƒŽ•‘ ”‡Ž‡˜ƒ– ˆ‘” ƒ “—‹”‡† ‡–ƒ„‘Ž‹  †‹•‡ƒ•‡Ǥ  –Š‡ ‘–Š‡” Šƒ†ǡ ”‡•‡ƒ” Š‹ƒ “—‹”‡†‡–ƒ„‘Ž‹ †‹•‡ƒ•‡ ƒƒ‹†‹—†‡”•–ƒ†‹‰

(72) •ǤŠ—•ǡ‡–Š‘†•–‘•–—†› „‘–Š–›’‡•‘ˆ†‹•‡ƒ•‡™‘—Ž†‹ Ž—†‡–Š‡—•‡‘ˆ‘‹ •ƒ’’”‘ƒ Š‡•ƒ† ‘’—–ƒ–‹‘ƒŽ‘†‡Ž‹‰Ǥ

(73)  ˆƒ –ǡ ‡™„‘” • ”‡‡‹‰ ‡ˆˆ‘”–• —•‡ Ǧ„ƒ•‡† –‡ Š‹“—‡• ˆ‘” –ƒ”‰‡–‡† ‡–ƒ„‘Ž‘‹ •ǡ ‘–ƒ„Ž›ˆ‘”–Š‡‡ƒ•—”‡‡–‘ˆ’Žƒ•ƒƒ‹‘ƒ ‹†ǡ’Žƒ•ƒƒ ›ŽǦ ƒ”‹–‹‡ƒ†—”‹‡‘”‰ƒ‹  ƒ ‹†’”‘ˆ‹Ž‡•ǤŠ‹•Šƒ•‰”‡ƒ–Ž›‹ ”‡ƒ•‡†–Š‡—„‡”‘ˆ

(74) •†‹• ‘˜‡”‡†‹–Š‡Žƒ•–ʹͲ›‡ƒ”• ȏ͸ǡͳͲǡͳͺǡͳ͵ͶȐǤŠ‹•ƒŽ•‘Ž‡†–‘–Š‡‹†‡–‹ˆ‹ ƒ–‹‘‘ˆ™‡ƒ‡”—–ƒ–‹‘•ˆ‘”™Š‹ Š‹–™ƒ•— Ž‡ƒ” ‹ˆ–Š‡›‰‹˜‡”‹•‡–‘†‹•‡ƒ•‡Ǥ ‘”‡šƒ’Ž‡ǡƒˆ–‡”–Š‡‹–”‘†— –‹‘‘ˆ‡™„‘”• ”‡‡‹‰ˆ‘”  †‡ˆ‹ ‹‡ ‹‡•ǡ •‡˜‡”ƒŽ ˜ƒ”‹ƒ–• ‘ˆ –Š‡ ACADM ‰‡‡ ™‡”‡ †‹• ‘˜‡”‡† ™‹–Š ‘”‡ –Šƒ ͳͲΨ ”‡•‹†—ƒŽƒ –‹˜‹–›ǡˆ‘”™Š‹ Š–Š‡‡‡†ˆ‘”–”‡ƒ–‡–‹•†‹•’—–‡†ȏͳ͵ͶȐǤŠ‹•™‘—Ž†„‡‹Ž‹‡™‹–Š ACADM•–Šƒ–ƒ••‘ ‹ƒ–‡™‹–ŠͺǦ ƒ”‹–‹‡Ž‡˜‡Ž•‹Š‡ƒŽ–Š›‹†‹˜‹†—ƒŽ•ȏͳͺǡͳ͵͵ȐǤ ƒ›‡–ƒ„‘Ž‹–‡•–Šƒ–’Žƒ›ƒ”‘Ž‡‹ƒ “—‹”‡†‡–ƒ„‘Ž‹ †‹•‡ƒ•‡•Šƒ˜‡ƒŽ•‘„‡‡‹†‡–‹ˆ‹‡†ƒ• ‡› ‘†‹ˆ‹‡”• ‹

(75) •Ǥ Š‡•‡ ‹ Ž—†‡ Ϊǡ ƒ‹‘ ƒ ‹†•ǡ ƒ† ‘‡œ›‡ Ǥ Ϊ Šƒ• „‡‡ ͳ͹.

(76) Chapter 1 ‹’Ž‹ ƒ–‡† ‹

(77) • „‡ ƒ—•‡ ‘ˆ ‹–• ƒ„‹Ž‹–› –‘ ƒ –‹˜ƒ–‡ •‹”–—‹• ȋ

(78) •Ȍ ȏͳ͵ͷȂͳ͵͹ȐǤ 

(79) • ƒ †‡ƒ ‡–›Žƒ–‡ƒ††‡ƒ ›Žƒ–‡’”‘–‡‹•ǡ‹ Ž—†‹‰‡œ›‡•ǡ ™Š‹ Šƒ›”‡•—Ž–‹ Šƒ‰‡•‹–Š‡ ƒ–ƒŽ›–‹  ’”‘’‡”–‹‡• ‘ˆ ‡œ›‡• ȏͳ͵ͷȂͳͶʹȐǤ ‘” ‡šƒ’Ž‡ 

(80) ͵Ǧ ƒ–ƒŽ›œ‡† †‡ƒ ‡–›Žƒ–‹‘ ‘ˆ Ž‘‰Ǧ Šƒ‹Ǧƒ†˜‡”›ǦŽ‘‰Ǧ Šƒ‹ƒ ›ŽǦ‘†‡Š›†”‘‰‡ƒ•‡•ȋƒ†ǡ”‡•’‡ –‹˜‡Ž›Ȍ ƒ†͵Ǧ ›†”‘š›Ǧ͵Ǧ‡–Š›Ž‰Ž—–ƒ”›Ž‘›–Šƒ•‡ʹȋ  ʹȌ‘š‹†ƒ–‹‘‹ ”‡ƒ•‡•–Š‡ƒ –‹˜‹–› ‘ˆ –Š‡•‡ ‡œ›‡• ȏͳ͵ͻǡͳͶͲȐǤ  ʹ ‹• ‹˜‘Ž˜‡† ‹ ‡–‘‰‡‡•‹•Ǥ 

(81) ͵ ƒŽ•‘ †‡ƒ ‡–›Žƒ–‡• ƒ––Š‡•ƒ‡ ‘•‡”˜‡†Ž›•‹‡”‡•‹†—‡‡ƒ”–Š‡ƒ –‹˜‡•‹–‡–Šƒ–‹•ƒ ‡–›Žƒ–‡†‹ ƒ†ȏͳͶͲȐǤ‘‘—”‘™Ž‡†‰‡‹–Šƒ•ǡŠ‘™‡˜‡”ǡ‘–„‡‡‹˜‡•–‹‰ƒ–‡†™Š‡–Š‡”–Š‹•ƒˆˆ‡ –• –Š‡ ƒ–ƒŽ›–‹  ƒ’ƒ ‹–› ‘ˆ Ǥ Š‡ ”‘Ž‡ ‘ˆ 

(82) •ƒ†Ϊ ‹

(83) • ƒ‡•–Š‡ ’‘–‡–‹ƒŽ –Š‡”ƒ’‡—–‹ –ƒ”‰‡–•ȏͳ͵͹ǡͳͶ͵ǡͳͶͶȐǤŽ–‡”‡†ƒ‹‘ƒ ‹†Ž‡˜‡Ž•Šƒ˜‡ƒŽ•‘„‡‡”‡’‘”–‡†‹

(84) • ‘–Š‡”–Šƒ–Š‡ƒ‹‘ƒ ‹†‘’ƒ–Š‹‡•Ǥ‘‡œ›‡ǡ™Š‹ Š‹•ƒŽ•‘ƒ ‘ˆƒ –‘”‹•‡˜‡”ƒŽ

(85) •Šƒ• ”‡ ‡–Ž›‰ƒ‹‡† ‘•‹†‡”ƒ„Ž‡ƒ––‡–‹‘ƒ•ƒ‘†‹ˆ‹‡”‹

(86) •ǡ‡‹–Š‡”˜‹ƒ‹–•ˆ”‡‡ˆ‘”ȋ‘ Ȍ ‘”‹–•‡•–‡”‹ˆ‹‡†ˆ‘”ȋ‘‡•–‡”Ȍȏͷͻǡ͸ͲȐǤ . Computational modeling and omics in IEMs ‘’—–ƒ–‹‘ƒŽ‘†‡Ž‹‰ǡ‹ ‘„‹ƒ–‹‘™‹–Š–Š‡—•‡‘ˆ‘‹ •–‡ Š‹“—‡•™‘—Ž†ƒŽ•‘„‡ƒ ‹’‘”–ƒ––‘‘Ž‹‘”†‡”–‘‰ƒ‹‹•‹‰Š–‹–‘–Š‡‡ Šƒ‹••—†‡”Ž›‹‰†‹•‡ƒ•‡’”‡•‡–ƒ–‹‘ ‹

(87) •Ǥ

(88) †‡‡†ǡƒ‡ ‘ͳǦ†‡”‹˜‡†ȏͳͶͷȐ‰‡‘‡Ǧ• ƒŽ‡•–‘‹ Š‹‘‡–”‹ ‘†‡Ž‘ˆ–Š‡Š—ƒ •ƒŽŽ‹–‡•–‹ƒŽ‡’‹–Š‡Ž‹ƒŽ ‡ŽŽ• ‘””‡ –Ž›’”‡†‹ –‡†–Š‡‘™„‹‘ƒ”‡”•‹͹ʹΨ‘ˆ–Š‡͵͸ •‹—Žƒ–‡†

(89) •ȏͳͶ͸Ȑǡ™Š‹Ž‡ƒ‘†‡Ž‘ˆ–Š‡Š—ƒŠ‡’ƒ–‘ ›–‡ ‘””‡ –Ž›’”‡†‹ –‡†ƒ„‘—–ŠƒŽˆ ‘ˆ–Š‡͵ͺ•‹—Žƒ–‡†

(90) •ȏͻͻȐǤˆ–‡”‘—”‰”‘—’ —”ƒ–‡†–Š‡ˆŽƒ˜‘’”‘–‡‘‡‹‡ ‘ʹǤʹǡ–Š‡ ‘†‡Ž ”‡ƒ Š‡† ͹ͶΨ ƒ —”ƒ › ‹ „‹‘ƒ”‡” ’”‡†‹ –‹‘ ˆ‘” Ͷͷ ˆŽƒ˜‘’”‘–‡‘‡Ǧ”‡Žƒ–‡†

(91) • ȏͳͳʹȐǤ‘’—–ƒ–‹‘ƒŽ†›ƒ‹ ‘†‡Ž‹‰‘ˆ

(92) •‹•”ƒ”‡Ǥ—”‰”‘—’Šƒ•ǡŠ‘™‡˜‡”ǡ‰‡‡”ƒ–‡† ƒ†›ƒ‹ ‘†‡Ž‘ˆ‹–‘ Š‘†”‹ƒŽˆƒ––›Ǧƒ ‹†‘š‹†ƒ–‹‘™Š‹ Š ‘—Ž†’”‡†‹ ––Š‡„‹‘ Š‡‹ ƒŽ ’Š‡‘–›’‡ ‘ˆ  ƒ† —Ž–‹’Ž‡ ƒ ›ŽǦ‘ †‡Š›†”‘‰‡ƒ•‡ †‡ˆ‹ ‹‡ › ȏͳͲͶǡͳͲ͹ǡͳͶ͹ȐǤ ‘ ‘†‡Ž ‡–ƒ„‘Ž‹  ƒ†ƒ’–ƒ–‹‘• ‹

(93) • ƒ† ‡˜‡ –Š‡ ’Š‡‘–›’‡ ‘ˆ ‹†‹˜‹†—ƒŽ ’ƒ–‹‡–•ǡ –Š‡ ‹ ‘”’‘”ƒ–‹‘‘ˆ‘‹ •†ƒ–ƒ™‹ŽŽ„‡‹’‘”–ƒ–Ǥ

(94) –Šƒ•„‡‡’”‘’‘•‡†–Šƒ–ƒ ‘„‹ƒ–‹‘‘ˆ Š‹‰ŠǦ–Š”‘—‰Š’—–‘‹ •ƒƒŽ›•‹•‹ ‘„‹ƒ–‹‘™‹–Š ‘’—–ƒ–‹‘ƒŽ‘†‡Ž‹‰ ‘—Ž†’”‘˜‹†‡ ˆ‘”ˆƒ•–‡”ƒ†‘”‡ƒ —”ƒ–‡†‹ƒ‰‘•‡•ƒ†•—„•‡“—‡––”‡ƒ–‡–ȏͳͶͺȐǤ . Mitochondrial fatty-ĂĐŝĚɴ-oxidation (mFAO) and mFAO deficiency ”‘ –Š‡ ’”‡˜‹‘—• •‡ –‹‘• ‹– ‹• ‡˜‹†‡– –Šƒ– ‹–‘ Š‘†”‹ƒŽ ˆƒ––›Ǧƒ ‹† ‘š‹†ƒ–‹‘ ‹• ƒ ‹’‘”–ƒ– ’ƒ–Š™ƒ› ‹ „‘–Š ƒ “—‹”‡† ƒ† ‹„‘” ‡–ƒ„‘Ž‹  †‹•‡ƒ•‡Ǥ –—†›‹‰   ‘—Ž† –Š‡”‡ˆ‘”‡”‡˜‡ƒŽ˜ƒŽ—ƒ„Ž‡‹•‹‰Š–•‹–‘–Š‡‡ Šƒ‹••—†‡”Ž›‹‰„‘–Š–›’‡•‘ˆ†‹•‡ƒ•‡•Ǥ ‹–‘ Š‘†”‹ƒŽˆƒ––›Ǧƒ ‹†‘š‹†ƒ–‹‘ǡ‘”‡•’‡ ‹ˆ‹ ƒŽŽ›‹–‘ Š‘†”‹ƒŽˆƒ––›Ǧƒ ‹†ȾǦ‘š‹†ƒ–‹‘‹• –Š‡ › Ž‹  ‘š‹†ƒ–‹‘ ‘ˆ ƒ –‹˜ƒ–‡† ˆƒ––› ƒ ‹†• ȋƒ ›ŽǦ‘ ‡•–‡”•Ȍ –‘ ƒ ‡–›ŽǦ‘Ǥ Š‡ DzȾdz ‹ DzȾǦ ‘š‹†ƒ–‹‘dz”‡Žƒ–‡•–‘–Š‡ˆƒ ––Šƒ––Š‡„‘†„‡–™‡‡–Š‡Ƚȋ–Š‡•‡ ‘† ƒ”„‘Ȍƒ†Ⱦ ƒ”„‘ ȋ–Š‹”† ƒ”„‘Ȍ‘ˆ–Š‡ƒ –‹˜ƒ–‡†ˆƒ––›Ǧƒ ‹†‹•„”‘‡†—”‹‰‡ƒ Š”‘—†‘ˆ–Š‡‘š‹†ƒ–‹‘ › Ž‡•ǡ –Š‡”‡„› ‰‡‡”ƒ–‹‰ ƒ ‡–›ŽǦ‘ ƒ† ƒ •Š‘”–‡‡† ƒ ›ŽǦ‘ ‡•–‡”Ǥ   ‹• ’ƒ”–‹ —Žƒ”Ž› ‹’‘”–ƒ–†—”‹‰’”‘Ž‘‰‡†’‡”‹‘†•‘ˆˆƒ•–‹‰‘”Š‹‰Š‡‡”‰›†‡ƒ†ǡ•— Šƒ•‡š‡” ‹•‡ƒ† ‘Ž†‡š’‘•—”‡Ǥ

(95) –Š‡•‡ ‘†‹–‹‘•ǡ ‹–Š‡Ž‹˜‡”’Žƒ›•ƒ’”‘‹‡–”‘Ž‡„›’”‘˜‹†‹‰ ˆ‘” ‰Ž— ‘‡‘‰‡‡•‹• ƒ† ’”‡ —”•‘”• ˆ‘” ‡–‘‰‡‡•‹•Ǥ Š‹• ‡ƒ„Ž‡• –Š‡ Ž‹˜‡” –‘ ’”‘˜‹†‡ –Š‡ ’‡”‹’Š‡”ƒŽ–‹••—‡•™‹–Š‰Ž— ‘•‡ƒ†‡–‘‡„‘†‹‡•ƒ•ˆ—‡ŽǤ‡™‹ŽŽ–Š‡”‡ˆ‘”‡Ž‘‘‹–‘Š‡’ƒ–‹   „‹‘ Š‡‹•–”›‹‘”‡†‡–ƒ‹Žȋ ‹‰—”‡ͳȌǤ. ͳͺ.

(96) General introduction and outline of the thesis. 1. Malonyl-CoA. Palmitoyl-CoA. Acyl-carnitine. carnitine. CoASH carnitine. CPT1 CACT. C16. CPT2. C4-C16. Mitochondrion. C4-C16. carnitine. CoASH carnitine. Acyl-carnitine Acyl-CoA. MCKAT C4-C16. Acetyl-CoA CoASH. SCAD. MCAD. LCAD. VLCAD. C4-C6. C4-C12. C8-C16. C12-C16. Enoyl-CoA. Ketoacyl-CoA. MSCHAD C4-C16. NADH + H+ NAD+. H2 O C4-ketoacyl-CoA. CROT C4-C16. Hydroxyacyl-CoA. FAD FADH2. Acetyl-CoA NADH + H+ C4-ketoacyl-CoA NAD+ CoASH. MTP C8-C16. . Figure 1. Schematic representation of the rodent mFAO pathway. ”‡‡ǣ‡œ›‡•’ƒ”–‹ ‹’ƒ–‹‰‹–Š‡ ƒ”‹–‹‡ › Ž‡Ǣ’—”’Ž‡ǣ‡œ›‡•’ƒ”–‹ ‹’ƒ–‹‰‹–Š‡•Š‘”–Ǧ Šƒ‹„”ƒ Šȋi.e.–Š‡ǦȀ Ǧ „”ƒ ŠȌǢ ‰”‡›ǣ ‡œ›‡• ’ƒ”–‹ ‹’ƒ–‹‰ ‹ –Š‡ ‡†‹—Ǧƒ† Ž‘‰Ǧ Šƒ‹ „”ƒ Š ȋi.e. –Š‡  „”ƒ ŠȌǤ ŽŽ ’”‘ ‡••‡•ƒ”‡”‡˜‡”•‹„Ž‡ƒ†–Š‡•‹œ‡‘ˆ–Š‡ƒ””‘™Š‡ƒ†•‹†‹ ƒ–‡•–Š‡‡–†‹”‡ –‹‘‘ˆ–Š‡”‡ƒ –‹‘•Ǥ.  ƒ––›ƒ ‹†•‘”‹‰‹ƒ–‹‰ˆ”‘–Š‡™Š‹–‡ƒ†‹’‘•‡–‹••—‡ȋȌ–›’‹ ƒŽŽ›Šƒ˜‡ƒ Šƒ‹Ž‡‰–Š‘ˆ ͳ͸‘”ͳͺ ƒ”„‘ƒ–‘•ǤŠ‡›ƒ”‡–ƒ‡—’‹–‘–Š‡Ž‹˜‡”ƒ†ƒ –‹˜ƒ–‡†„› ‘†‡•ƒ–‹‘™‹–Š ‘ Ǥ Š‹•ƒ –‹˜ƒ–‹‘ ‹• ƒ–ƒŽ›œ‡† „› ƒ ›ŽǦ‘ •›–Š‡–ƒ•‡•‘” ˆƒ––› ƒ ‹† –”ƒ•ˆ‡” ’”‘–‡‹• ȋ •Ȍƒ†‰‡‡”ƒ–‡•ƒ ›ŽǦ‘‡•–‡”•ȏͳͶͻǡͳͷͲȐǤŠ‡ƒ ›ŽǦ‘‡•–‡”•ƒ”‡•—„•‡“—‡–Ž›–ƒ‡ —’ ‹–‘ –Š‡ ‹–‘ Š‘†”‹ƒ ˆ‘” ‘š‹†ƒ–‹‘ –‘ ƒ ‡–›ŽǦ‘Ǥ Š‡ ƒ ‡–›ŽǦ‘ ƒ •—„•‡“—‡–Ž› „‡ ‘š‹†‹œ‡†ˆ‘”’”‘†— –‹‘‘”—•‡†ƒ•’”‡ —”•‘”ˆ‘”‡–‘‰‡‡•‹•Ǥ’–ƒ‡‘ˆƒ ›ŽǦ‘‡•–‡”• ‹–‘ –Š‡ ‹–‘ Š‘†”‹ƒŽ ƒ–”‹š ‘ —”• ˜‹ƒ –Š‡ ƒ”‹–‹‡ •Š—––Ž‡Ǥ Š‹• •Š—––Ž‡ ‘•‹•–• ‘ˆ –Š‡ ‡œ›‡• ƒ”‹–‹‡ ’ƒŽ‹–‘›Ž–”ƒ•ˆ‡”ƒ•‡

(97)  ȋͳȌǡ ƒ”‹–‹‡Ǧƒ ›ŽǦ ƒ”‹–‹‡ –”ƒ•Ž‘ ƒ•‡ ȋȌǡ ƒ† ƒ”‹–‹‡ ’ƒŽ‹–‘›Ž–”ƒ•ˆ‡”ƒ•‡

(98)

(99)  ȋʹȌǤ ‡”‡‹ǡ –Š‡ ›–‘•‘Ž‹  ƒ ›ŽǦ‘ ‹• ‘˜‡”–‡† –‘ ƒ ›ŽǦ ƒ”‹–‹‡ǡ „› ‘•—‹‰ Ǧ ƒ”‹–‹‡ ƒ† ”‡Ž‡ƒ•‹‰ ‘ Ǥ Š‡ ›–‘•‘Ž‹  ƒ ›ŽǦ ƒ”‹–‹‡‹••—„•‡“—‡–Ž›–”ƒ•Ž‘ ƒ–‡†‹–‘–Š‡‹–‘ Š‘†”‹ƒ–Š”‘—‰Š‹‡š Šƒ‰‡ ˆ‘”‹–‘ Š‘†”‹ƒŽǦ ƒ”‹–‹‡Ǥ ‡‹–Š‡‹–‘ Š‘†”‹ƒǡ–Š‡ƒ ›ŽǦ ƒ”‹–‹‡‹• ‘˜‡”–‡†„ƒ  –‘ ƒ ›ŽǦ‘ „› ʹǤ Š‡ ƒ ›ŽǦ‘ ‘Ž‡ —Ž‡ •—„•‡“—‡–Ž› —†‡”‰‘‡• ˆƒ––›Ǧƒ ‹† „‡–ƒǦ ‘š‹†ƒ–‹‘Ǥ‹–‘ Š‘†”‹ƒŽˆƒ––›Ǧƒ ‹†„‡–ƒǦ‘š‹†ƒ–‹‘ȋ Ȍ‘ —”•‹”‡’‡–‹–‹˜‡ˆ‘—”Ǧ”‡ƒ –‹‘ › Ž‡•ȋ ‹‰—”‡ͳȌǤ

(100) ‡ƒ Š”‘—†ǡ–Š‡ƒ ›ŽǦ‘‡•–‡”‹••Š‘”–‡‡†„›–™‘ ƒ”„‘ƒ–‘•ƒ†‘‡ ƒ ‡–›ŽǦ‘‹•’”‘†— ‡†ȏͳͷͳȂͳͷ͵ȐǤ‹ˆˆ‡”‡– › Ž‡•ƒ”‡ ƒ–ƒŽ›œ‡†„›–Š‡•ƒ‡•‡–‘ˆ‡œ›‡•Ǥ Š‹•‡ƒ•–Šƒ–‡ƒ Š ‡œ›‡ ƒ–ƒŽ›œ‡•–Š‡ ‘˜‡”•‹‘‘ˆˆƒ––›Ǧƒ ‹††‡”‹˜ƒ–‹˜‡•‘ˆ ƒ ”ƒ‰‡‘ˆ Šƒ‹Ž‡‰–Š•ȏͳͲͺǡͳͷ͵ȐǤœ›‡•–Šƒ– ƒ–ƒŽ›œ‡–Š‡ ‘˜‡”•‹‘‘ˆ—Ž–‹’Ž‡•—„•–”ƒ–‡• ƒ”‡ ƒŽŽ‡† ’”‘‹• —‘—•Ǥ‹ ‡ ‡ƒ Š   ‡œ›‡ ‹•’”‘‹• —‘—•ǡ –Š‡†‹ˆˆ‡”‡– •—„•–”ƒ–‡• ƒ†”‡•—Ž–‹‰’”‘†— –• ‘’‡–‡ˆ‘”„‹†‹‰–‘–Š‡ƒ –‹˜‡•‹–‡ǤŠ‡”‡ƒ”‡‡˜‡”–Š‡Ž‡••†‹ˆˆ‡”‡– ‹•‘‡œ›‡•ˆ‘”‡ƒ Š”‡ƒ –‹‘ǤŠ‡ˆ‹”•–”‡ƒ –‹‘‘ˆ‡ƒ Š › Ž‡‹• ƒ–ƒŽ›œ‡†„›†‹ˆˆ‡”‡–ƒ ›ŽǦ ‘†‡Š›†”‘‰‡ƒ•‡‹•‘‡œ›‡•ǣ–Š‡‡”›Ǧ‘‰Ǧǡ‘‰Ǧǡ‡†‹—Ǧǡƒ†Š‘”–ǦŠƒ‹ ›ŽǦ‘ ‡Š›†”‘‰‡ƒ•‡• ǡ ǡ ǡ ƒ† Ȍ ȋ•Ȍ ȋǤǤ ͳǤ͵ǤͻͻǤ͵ ƒ† ǤǤͳǤ͵ǤͺǤͳȌǤ ƒ Š ‘ˆ –Š‡•‡ ‹•‘‡œ›‡• ƒ ‡’–• ƒ ”ƒ‰‡ ‘ˆ ƒ ›ŽǦ‘ •—„•–”ƒ–‡• ‘ˆ †‹ˆˆ‡”‡–ǡ ‘˜‡”Žƒ’’‹‰ Šƒ‹Ž‡‰–Š•Ǥ‘†‡–•‡š’”‡••ƒŽŽˆ‘—”ƒ ›ŽǦ‘†‡Š›†”‘‰‡ƒ•‡‹•‘‡œ›‡•‹–Š‡Ž‹˜‡”ǡ™Š‹Ž‡ ‹ Š—ƒ Ž‹˜‡”  ‹•Ž‘™Ž› ‡š’”‡••‡† ȏͺͲȐ ƒ† ‘ˆ Ž‹‹–‡† ‹’‘”–ƒ ‡ ˆ‘” Š‡’ƒ–‹    ȏͳͷ͵ȐǤ

(101) ”‘†‡–•ǡ Šƒ‹ǦŽ‡‰–Š•’‡ ‹ˆ‹ ‹–‹‡•‘ˆ–Š‡•ƒ”‡ͳʹǦͳ͸ǡͺǦͳ͸ǡͶǦͳʹƒ†ͶǦ͸ ƒ”„‘. ͳͻ.

(102) Chapter 1 ƒ–‘• ˆ‘” ǡ ǡ  ƒ† ǡ ”‡•’‡ –‹˜‡Ž›ǡ ™Š‹Ž‡ ‹ Š—ƒ• –Š‡ Šƒ‹ǦŽ‡‰–Š •’‡ ‹ˆ‹ ‹–‹‡• ƒ”‡ ͸Ǧͳ͸ǡ ͶǦͳ͸ ƒ† ͶǦ͸ ˆ‘” ǡ  ƒ† ǡ ”‡•’‡ –‹˜‡Ž›Ǥ ‹ ‡ –Š‡ ‹•‘‡œ›‡•Šƒ˜‡‘˜‡”Žƒ’’‹‰ Šƒ‹ǦŽ‡‰–Š•’‡ ‹ˆ‹ ‹–‹‡•ǡ–Š‡› ‘’‡–‡ˆ‘”–Š‡‹”•—„•–”ƒ–‡•ƒ† ’”‘†— –•Ǥ‘‰‡–Š‡”™‹–Š–Š‡ › Ž‹ ƒ–—”‡‘ˆ–Š‡’ƒ–Š™ƒ›ǡ–Š‡˜ƒ•–„‹‘ Š‡‹ ƒŽ ‘’‡–‹–‹‘ ƒ‡• –Š‡   „‹‘ Š‡‹ ƒŽŽ› ’ƒ”–‹ —Žƒ”Ž› ‘’Ž‡šǤ Š‡ ’”‘†— – ‘ˆ –Š‡ ƒ ›ŽǦ‘ †‡Š›†”‘‰‡ƒ•‡•‹•‡‘›ŽǦ‘ȋ ‹‰—”‡ͳȌǤ‘›ŽǦ‘‡•–‡”•‘ˆͺ‘”‘”‡ ƒ”„‘ƒ–‘• ƒ„‡ ˆ—”–Š‡”‡–ƒ„‘Ž‹œ‡†„›ƒ•‹‰Ž‡‡œ›‡™‹–Š͵ƒ –‹˜‹–‹‡•‹–‘ Š‘†”‹ƒŽ”‹ˆ— –‹‘ƒŽ”‘–‡‹ ȋȌǤ

(103) ”‡ˆ‡”–‘–Š‹•ƒ•–Š‡‡†‹—Ǧƒ†Ž‘‰Ǧ Šƒ‹‘”„”ƒ Š‘ˆ–Š‡ ’ƒ–Š™ƒ›Ǥ Ž–‡”ƒ–‹˜‡Ž›ǡ –Š‡ ‡‘›ŽǦ‘ ‡•–‡” ƒ —†‡”‰‘ ˆ—”–Š‡” Šƒ‹Ǧ•Š‘”–‡‹‰ ƒ–ƒŽ›œ‡† „› ͵ •‡’ƒ”ƒ–‡‡œ›‡•ǣ‡‘›ŽǦ‘Š›†”ƒ–ƒ•‡‘” ”‘–‘ƒ•‡ȋǡǤǤͶǤʹǤͳǤ͹Ͷƒ†ǤǤͶǤʹǤͳǤͳͷͲȌǡ Š›†”‘š›ƒ ›ŽǦ‘ †‡Š›†”‘‰‡ƒ•‡ȋȀ ǡ ǤǤͳǤͳǤͳǤʹͳͳ ƒ†ǤǤ ͳǤͳǤͳǤ͵ͷȌ ƒ†‡†‹—Ǧ Šƒ‹ ͵Ǧ‡–‘Ǧƒ ›ŽǦ‘ –Š‹‘Žƒ•‡ ȋǡ ǤǤ ʹǤ͵ǤͳǤͳ͸ȌȌǡ ”‡•’‡ –‹˜‡Ž›Ǥ  ›ŽǦ‘ ‡•–‡”• ‘ˆ ƒŽŽ Šƒ‹Ž‡‰–Š• ƒ„‡‘š‹†‹œ‡†˜‹ƒ–Š‹•„”ƒ ŠǤ

(104) ”‡ˆ‡”–‘–Š‹•ƒ•–Š‡•Š‘”–Ǧ Šƒ‹„”ƒ Š‘”–Š‡ ǦȀ Ǧ„”ƒ ŠǤŠ‡”‡ƒ –‹‘• ƒ–ƒŽ›œ‡†„›Ȁ ƒ†”‡“—‹”‡ –Š‡ ‘‡œ›‡• Ϊ ƒ† ‘ ǡ ”‡•’‡ –‹˜‡Ž›Ǥ Ȁ  ‘š‹†‹œ‡• Š›†”‘š›ƒ ›ŽǦ‘ –‘ ‡–‘ƒ ›ŽǦ‘ ™‹–Š Ϊ ƒ• –Š‡ ‡Ž‡ –”‘ ƒ ‡’–‘”Ǥ Š‹• ”‡ƒ –‹‘ ‹• ”‡˜‡”•‹„Ž‡ ƒ† ‘’‡”ƒ–‡• Ž‘•‡–‘‡“—‹Ž‹„”‹—ȏͳͲͺȐ†—‡–‘‹–•Š‹‰Š ƒ–ƒŽ›–‹  ƒ’ƒ ‹–›Ǥ

(105) –Šƒ•ƒ˜‡”›•ƒŽŽ‡“—‹Ž‹„”‹— ‘•–ƒ–ȋʹǤͳ͹ȉͳͲǦͶȌƒ†–Š‡”‡ˆ‘”‡”‡“—‹”‡•ƒ˜‡”›Ž‘™’”‘†— –‘˜‡”•—„•–”ƒ–‡”ƒ–‹‘–‘”—‹ –Š‡ˆ‘”™ƒ”††‹”‡ –‹‘Ǥ

(106) –Š‡Žƒ•–”‡ƒ –‹‘‘ˆ–Š‡ › Ž‡ǡ ƒ–ƒŽ›œ‡†„›ǡ‘‹• ‘•—‡† ƒ†‡–‘ƒ ›ŽǦ‘‹••’Ž‹–‹–‘ƒƒ ›ŽǦ‘‡•–‡”–Šƒ–‹•–™‘ ƒ”„‘•Š‘”–‡”ƒ†ƒ ‡–›ŽǦ‘Ǥ Šƒ•ƒŠ‹‰Š‡“—‹Ž‹„”‹— ‘•–ƒ–‘ˆͳͲ͵ȏͳͷ͵ȐǤŠ‹•ƒŽŽ‘™•–‘ƒ‹–ƒ‹Ž‘™‡–‘ƒ ›ŽǦ ‘ ‘ ‡–”ƒ–‹‘•Ǥ ‘–ƒ„Ž›ǡ ǡ Ȁ  ƒ†  ƒŽ•‘ ƒ–ƒŽ›œ‡ –Š‡ ˆ‹ƒŽ –Š”‡‡ ”‡ƒ –‹‘• ‘ˆ –Š‡ ƒ–ƒ„‘Ž‹• ‘ˆ ‹•‘Ž‡— ‹‡ǣ –‘‰‡–Š‡”ǡ –Š‡•‡ ‡œ›‡• ‘˜‡”– –Š‡ ‹•‘Ž‡— ‹‡ ƒ–ƒ„‘Ž‹•‹–‡”‡†‹ƒ–‡‡–ƒ„‘Ž‹–‡–‹‰Ž›ŽǦ‘ȋ‹Ǥ‡ǤʹǦ‡–Š›Ž„—–ǦʹǦ‡‘›ŽǦ‘Ȍ–‘ʹǦ‡–Š›ŽǦ͵Ǧ Š›†”‘š›„—–›”›ŽǦ‘ǡ •—„•‡“—‡–Ž› –‘ ʹǦ‡–Š›Žƒ ‡–‘ƒ ‡–›ŽǦ‘ ƒ† –Š‡ –‘ ’”‘’‹‘›ŽǦ‘ ƒ†ƒ ‡–›ŽǦ‘ȏͳͷͶȂͳͷ͹ȐǤŠ‹•”‡•—Ž–•‹‡š–”ƒ•—„•–”ƒ–‡ ‘’‡–‹–‹‘ˆ‘”–Š‡•‡‡œ›‡•Ǥ ‘–Š‡” ‘’Ž‡š‹–›‹–Š‡ ’ƒ–Š™ƒ›‹••—„ ‡ŽŽ—Žƒ”Ž‘ ƒŽ‹œƒ–‹‘‘ˆ–Š‡‡œ›‡•ǤŠ‹Ž‡ ͳǡǡʹǡƒ†ƒ”‡Ž‘ ƒ–‡†ƒ––Š‡‹‡”‹–‘ Š‘†”‹ƒŽ‡„”ƒ‡ǡǡ ǡǡǡȀ ǡƒ†ƒ”‡—•—ƒŽŽ› ‘•‹†‡”‡†•‘Ž—„Ž‡ƒ†Ž‘ ƒŽ‹œ‡†‹ –Š‡ ‹–‘ Š‘†”‹ƒŽ ƒ–”‹š ȏͳͷ͵ȐǤ ‘™‡˜‡”ǡ ‡š’‡”‹‡–ƒŽ‡˜‹†‡ ‡ ‹ ”ƒ– Ž‹˜‡” ‹–‘ Š‘†”‹ƒ Šƒ••Š‘™–Šƒ–ǡƒ† ƒƒŽ•‘„‡’Š›•‹ ƒŽŽ›ƒ••‘ ‹ƒ–‡†–‘–Š‡‡„”ƒ‡Ǧ „‘—† ‘š‹†ƒ–‹˜‡ ’Š‘•’Š‘”›Žƒ–‹‘ ȋ Ȍ •—’‡” ‘’Ž‡š‡• ȏͳͷͺȐǤ

(107) – ™ƒ• •—‰‰‡•–‡† –Šƒ– –Š‡‹” ‹–”ƒ ‡ŽŽ—Žƒ” Ž‘ ƒŽ‹œƒ–‹‘ ƒ› „‡ ‘†‹–‹‘ †‡’‡†‡– ȏͳͷͺȐǤ ǡ Ȁ  ƒ† Šƒ˜‡ƒŽ•‘„‡‡•Š‘™–‘„‹††‹”‡ –Ž›‘”‹†‹”‡ –Ž›–‘–Š‡‹–‘ Š‘†”‹ƒŽ‡„”ƒ‡ ȋ™‹–Š •—„•–ƒ–‹ƒŽ Ͷ ƒ –‹˜‹–› ƒ– –Š‡ ‡„”ƒ‡ ˆ‘” ƒŽŽ –Š‡•‡ ‡œ›‡•Ȍ ȏͳͷͻȐǤ

(108) –‡”‡•–‹‰Ž›ǡ •—„•–ƒ–‹ƒŽŽ› Š‹‰Š‡” ”‡•’‹”ƒ–‹‘ǦŽ‹‡† ‘š‹†ƒ–‹‘ ‘ˆ „—–›”›ŽǦ‘ǡ „—–‡‘›ŽǦ‘ ƒ† Š›†”‘š›„—–›”›ŽǦ‘ Šƒ• „‡‡ ”‡’‘”–‡† ‹ ‰‡–Ž›Ǧ†‹•”—’–‡† ‘’ƒ”‡† –‘ ‘’Ž‡–‡Ž›Ǧ †‹•”—’–‡† ‹–‘ Š‘†”‹ƒ ȏͳ͸ͲȐǤ —”–Š‡”‘”‡ǡ ’Š›•‹ ƒŽ ƒ••‘ ‹ƒ–‹‘• „‡–™‡‡ Ȁ  ƒ†  †‡Š›†”‘‰‡ƒ•‡ȋ‘’Ž‡š

(109) ȌǡȀ ƒ†–Š‡‡–‘‰‡‡•‹•‡œ›‡  ʹȋ‘’Ž‡š

(110) Ȍ ƒ† „‡–™‡‡  ƒ† –Š‡ ƒ ‡–›ŽǦ‘Ǧ ‘•—‹‰  › Ž‡ ‡œ›‡ ‹–”ƒ–‡ •›–Šƒ•‡ Šƒ˜‡„‡‡†‡‘•–”ƒ–‡†ȏͳ͸ͳȂͳ͸͵ȐǤŠ‹••—‰‰‡•–•ƒ‡ˆˆ‹ ‹‡–‡ Šƒ‹•ˆ‘”–Š‡”‡‘š‹†ƒ–‹‘ ‘ˆ  ǡ –Š‡ ”‡‰‡‡”ƒ–‹‘ ‘ˆ ‘  ˆ”‘ ƒ ‡–›ŽǦ‘ „› ‹–”ƒ–‡ •›–Šƒ•‡ ‘” –Š‡ ‡–‘‰‡‹  ’ƒ–Š™ƒ› ˆ‘” ‹•–ƒ ‡ ƒ† ”‡‘˜ƒŽ ‘ˆ ͶǦ‡–‘ƒ ›ŽǦ‘ ‹–‘ ‡–‘‰‡‡•‹•Ǥ Š—•ǡ ’‘–‡–‹ƒŽŽ›   •‘Ž—„Ž‡ ‡œ›‡• ƒ› •’ƒ–‹ƒŽŽ› ‘”‰ƒ‹œ‡ ‹ •— Š ƒ ƒ‡” –Šƒ– Š‹‰Š‡” ˆƒ––›Ǧƒ ‹† ‘š‹†ƒ–‹‘”ƒ–‡• ƒ„‡ƒ Š‹‡˜‡†ǡ’ƒ”–‹ —Žƒ”Ž›‹ ‘†‹–‹‘•‘ˆŠ‹‰ŠǦ‡‡”‰›†‡ƒ†Ǥ ʹͲ.

(111) General introduction and outline of the thesis. 1. . mFAO deficiency ƒ–Š‘Ž‘‰‹ ƒŽ ‹„‘” ‡””‘”• Šƒ˜‡ „‡‡ ‹†‡–‹ˆ‹‡† ˆ‘” ƒŽŽ ‡œ›‡• ‘ˆ –Š‡   ’ƒ–Š™ƒ› ȏͳͷ͵ǡͳ͸ͶȐǤ

Referenties

Download het nu ( PDF - 276 pagina - 3.15 MB )

GERELATEERDE DOCUMENTEN

University of Groningen Exploring the mechanisms underlying the phenotype of MCAD deficiency with Systems Medicine Martines, Anne-Claire

Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the authors and/or

University of Groningen Exploring the mechanisms underlying the phenotype of MCAD deficiency with Systems Medicine Martines, Anne-Claire

Exploring the mechanisms underlying the phenotype of MCAD deficiency with Systems Medicine: from computational model to mice to man..

00 0 0

Met het eindigen van de Kaderwet in 2003 en door het goede van de Kaderwet onder te brengen in een vernieuwde en aangescherpte WGR wordt het mogelijk de

0 0 00

Het is wenselijk dat ouderen die kiezen voor minder uren werken of in een andere functie een stapje terugdoen met bijbehorend lager salaris, hiervoor niet gestraft

3 0 0 0 0

Zo hebben de Surinaamse jongeren uit de onderzoekgroep vaker problemen met hun moeder, de Turkse en Marokkaanse jongeren vaker met hun vader, In belangrijke mate wordt dit

ggapp >0, 1, >0, >0, 1 ≠≠ loglog apa =⋅ gga >0, 1, >0 ≠ logloglog −= ggab >0, 1, >0, >0 ≠ aabb ggab >0, 1, >0, >0 ≠ k'xf'gxg'x ()(())() =⋅ pxfxgx ()()() =⋅ p'xf'xgxfxg'x ()()()()() =⋅+⋅ EXnp () =⋅ X

[r]

 logloglog aag logloglog  ggab >0, 1, >0, >0  aabb ggab >0, 1, >0, >0 

In tabel 1 staan gegevens van drie wasdrogers: een energiezuinige wasdroger met een A-label en twee veel verkochte “gewone” wasdrogers met een C-label.. De jaarkosten van een

ggapp >0, 1, >0, >0, 1 ≠≠ loglog apa =⋅ gga >0, 1, >0 ≠ logloglog −= ggab >0, 1, >0, >0 ≠ aabb logloglog abab += ggab >0, 1, >0, >0 ≠ EXnp () =⋅ X

Met behulp van deze tabel kan men de vraag beantwoorden of het in de groep vrouwelijke werknemers boven de 40 relatief vaker voorkomt dat iemand zich wel eens oneerlijk