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

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

(3)

(4) 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

(5)  ƒ††‹–‹‘ǡ ͳͳ. 1.

(6) 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

(7) 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

(8) ™‹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

(9) 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

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

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

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

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

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

(15) 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.

(16) 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

(17) –‹•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

(18) –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

(19) –™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

(20) – 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

(21) ”‡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

(22)  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.

(23) 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

(24) –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.

(25) 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 

(26) 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

(27) – ‘–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.

(28) 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

(29) 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

(30) – ‹• ‹’‘”–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

(31) „‘” ‡””‘”• ‘ˆ ‡–ƒ„‘Ž‹• ȋ

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

(33) •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‡

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

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

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

(37) –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–‡† –‘

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

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

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

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

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

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

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

(45) •ȏͳͺǡͳ͵ͳǡͳ͵ʹȐǤ

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

(47) –‘‰‡–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

(48) –‹• –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

(49) • ”‡•—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‡•–—†›‹‰

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

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

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

(53) •Ǥ††‹–‹‘ƒŽŽ›ǡ–Š‡•–—†›‘ˆ

(54) •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†‹‰

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

(56)  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

(57) •†‹• ‘˜‡”‡†‹–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‹‡”• ‹

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

(59) Chapter 1 ‹’Ž‹ ƒ–‡† ‹

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

(61) •Ȍ ȏͳ͵ͷȂͳ͵͹ȐǤ 

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

(63) ͵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 

(64) ͵ 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 

(65) •ƒ†Ϊ ‹

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

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

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

(69) •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–‹‘ ‹

(70) •Ǥ

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

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

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

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

(75) •‹•”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–‹‘• ‹

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

(77) –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

(78) –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.

(79) 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•‡

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

(81)

(82)  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

(83) ‡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

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

(85) 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

(86) ”‡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

(87) ”‡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

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

(89) –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

(90) – ™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

(91) –‡”‡•–‹‰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

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

(93) 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.

(94) 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

(95) ˆ —–”‡ƒ–‡†ǡ  Ǧ†‡ˆ‹ ‹‡– ‹†‹˜‹†—ƒŽ• ”— ƒ ”‹• ‘ˆ •‡˜‡”‡ǡ Ž‹ˆ‡Ǧ–Š”‡ƒ–‡‹‰ Š›’‘‡–‘–‹  Š›’‘‰Ž› ‡‹ƒ †—”‹‰ ˆƒ•–‹‰ ‘” ‡‡”‰›Ǧ†‡ƒ†‹‰ ‘†‹–‹‘•Ǥ ǡ ǡ ƒ†  ƒ ‹ ’”‹ ‹’Ž‡ –ƒ‡ ‘˜‡” ‡ƒ Š ‘–Š‡”ǯ• ”‘Ž‡ǡ †—‡ –‘ –Š‡‹” ‘˜‡”Žƒ’’‹‰ •—„•–”ƒ–‡ •’‡ ‹ˆ‹ ‹–‹‡•ȏͳͲͻǡͳͷ͵ȐǡƒŽ„‡‹–™‹–ŠŽ‡••‡”ƒˆˆ‹‹–›ƒ†ƒ––Š‡‡š’‡•‡‘ˆ ƒ’ƒ ‹–›ˆ‘”–Š‡‹”‘™ ˆ— –‹‘Ǥ —”–Š‡”‘”‡ǡƒ†‡ˆ‹ ‹‡ ›‘ˆ‹Š‹„‹–• ƒŽ”‡ƒ†›‹–Š‡„‡‰‹‹‰ǡ™Š‹Ž‡ ‹  †‡ˆ‹ ‹‡ › ƒ†  †‡ˆ‹ ‹‡ › –Š‡ ˆ‹”•– › Ž‡• ‘ˆ –Š‡ EǦ‘š‹†ƒ–‹‘ ƒ ’”‘ ‡‡† ‘”ƒŽŽ›ǤŠ—•ǡ™Š‡‘”ƒ”‡†‡ˆ‹ ‹‡–ǡ•‘‡ ‹„„•‡‡”‰› ƒ•–‹ŽŽ„‡Šƒ”˜‡•–‡† ˆ”‘ ƒ ’ƒ”–‹ƒŽ EǦ‘š‹†ƒ–‹‘Ǥ Š‹• ƒ› ‡š’Žƒ‹ ™Š› Ǧ†‡ˆ‹ ‹‡– ȋȌ Š‹Ž†”‡ǡ ™Š‘ ™‘—Ž†‘Ž›„‡†‡ˆ‹ ‹‡–‹–Š‡Žƒ•–  › Ž‡ǡ‘ˆ–‡Šƒ˜‡‘Ž›‹‘”•›’–‘•ȏͳͷ͵Ȑƒ† ™Š› –Š‡ •‡˜‡”‹–› ‘ˆ †‹•‡ƒ•‡ ’”‡•‡–ƒ–‹‘ ‰‡‡”ƒŽŽ› ‹ ”‡ƒ•‡• ˆ”‘  –‘  –‘  ȏͳͷ͵ȐǤ ƒ•‡† ‘ ”‡’‘”–‡† Ž‹‹ ƒŽ ’”‡•‡–ƒ–‹‘ǡ  ƒ› „‡ ”‡‰ƒ”†‡† ƒ• Ž‡•• •‡˜‡”‡–Šƒƒ†‘”‡•‡˜‡”‡–Šƒȏͳͷ͵ǡͳ͸ͷȐǤŠƒ•„‡‡ƒ••‘ ‹ƒ–‡† ™‹–ŠŠ›’‘‡–‘–‹ Š›’‘‰Ž› ‡‹ƒǡ ƒ”†‹‘›‘’ƒ–Š›ǡ ƒ”†‹ƒ ƒ””›–Š‹ƒ•ƒ† ‘†— –‹‘†‡ˆ‡ –•ǡ •‡Ž‡–ƒŽ ›‘’ƒ–Š› ƒ† ”Šƒ„†‘›‘Ž›•‹•Ǥ  Šƒ• „‡‡ ’”‡†‘‹ƒ–Ž› ƒ••‘ ‹ƒ–‡† ™‹–Š Š›’‘‡–‘–‹  Š›’‘‰Ž› ‡‹ƒǤ  Šƒ• ‘ Ž‡ƒ” ’ƒ–Š‘Ž‘‰‹ ƒŽ ’Š‡‘–›’‡ ƒ† ‹• ‰‡‡”ƒŽŽ› ”‡‰ƒ”†‡†ƒ•ƒ†‡ˆ‹ ‹‡ ›™‹–Š“—‡•–‹‘ƒ„Ž‡ Ž‹‹ ƒŽ•‹‰‹ˆ‹ ƒ ‡ȏͳͷ͵ǡͳ͸ͷǡͳ͸͸ȐǤ ‘™‡˜‡”ǡƒ• ’”‡˜‹‘—•Ž›‹†‹ ƒ–‡†ˆ‘”

(96) •‹‰‡‡”ƒŽǡ–Š‡”‡‹•ƒŽƒ”‰‡Š‡–‡”‘‰‡‡‹–›‹†‹•‡ƒ•‡’”‡•‡–ƒ–‹‘ „‡–™‡‡  Ǧ†‡ˆ‹ ‹‡– ‹†‹˜‹†—ƒŽ• ™‹–Š –Š‡ •ƒ‡ ‡œ›‡ †‡ˆ‹ ‹‡ ›ǡ ƒ† ‡˜‡ ™‹–Š –Š‡ •ƒ‡‰‡‡–‹ —–ƒ–‹‘ȏͳ͵Ͷǡͳͷ͵ǡͳ͸ͷǡͳ͸͹Ȃͳ͹ͳȐǤ . Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency  †‡ˆ‹ ‹‡ › ȋ

(97)  ʹͲͳͶͷͲȌ ‹• –Š‡ ‘•– ‘‘   †‡ˆ‡ –ǡ ™‹–Š ƒ ‘„•‡”˜‡† ’”‡˜ƒŽ‡ ‡ ‘ˆ —’ –‘ ͳ ‹ ͸͸ͲͲ ‡™„‘”• ȏͳͳǡͳ͵ͲȐǤ

(98)  —–”‡ƒ–‡† ‹†‹˜‹†—ƒŽ•  Šƒ• ƒ †‹•‡ƒ•‡ •‡˜‡”‹–› –Šƒ– ”ƒ‰‡• ˆ”‘ ‘’Ž‡–‡Ž› ƒ•›’–‘ƒ–‹  –‘ ˆƒ–ƒŽǤ ’ƒ”– ˆ”‘ Šƒ˜‹‰ ƒ Ž‹‹ ƒŽ”‡Ž‡˜ƒ ‡‹‹–•‘™”‹‰Š–ǡƒ›–Š‡”‡ˆ‘”‡ƒŽ•‘‘ˆˆ‡”‹•‹‰Š–•‹–Š‡‘†‹ˆ›‹‰ ˆƒ –‘”• ‘ˆ   ˆ— –‹‘Ǥ Š‹• ™‘—Ž† „‡ ‹’‘”–ƒ– ˆ‘” —†‡”•–ƒ†‹‰ ‘–Š‡”   †‡ˆ‹ ‹‡ ‹‡•ƒ†‡–ƒ„‘Ž‹ †‹•‡ƒ•‡‹‰‡‡”ƒŽǤ

(99) †‹˜‹†—ƒŽ• Š‘‘œ›‰‘—• ˆ‘” –Š‡ Ž‘••Ǧ‘ˆǦˆ— –‹‘ Ǥͻͺͷε  —–ƒ–‹‘ ‹ –Š‡ ACADM ‰‡‡ǡ ‡ ‘†‹‰ ǡ ƒ ‘—– ˆ‘” ͹͹Ψ ‘ˆ –Š‡ ƒ•‡• ȏͳ͵ͶȐǤ Š‹• —–ƒ–‹‘ ƒ—•‡• ƒ Šƒ‰‡ ˆ”‘ Ž›•‹‡–‘‰Ž—–ƒƒ–‡ƒ–’‘•‹–‹‘͵ͲͶȋ’Ǥ͵ͲͶȌ‹–Š‡ƒ–—”‡ǤŠ‹•”‡•—Ž–•‹‹’ƒ‹”‡† ’”‘–‡‹ ˆ‘Ž†‹‰ǡ †‡ ”‡ƒ•‡† ’”‘–‡‹ •–ƒ„‹Ž‹–› ƒ† •‡˜‡”‡Ž› ‹’ƒ‹”‡†  ‡œ›‡ ƒ –‹˜‹–› ȏͳ͹ʹȂͳ͹ͷȐǤŠ‹Ž†”‡‹–Š‹•‰”‘—’”—ƒ•‡˜‡”‡”‹•‘ˆŽ‹ˆ‡Ǧ–Š”‡ƒ–‡‹‰Ž‘™„Ž‘‘†‰Ž— ‘•‡ƒ† ‡–‘‡ „‘†‹‡• ‘ ‡–”ƒ–‹‘• ȋŠ›’‘‡–‘–‹  Š›’‘‰Ž› ‡‹ƒȌ ȏͳͷ͵ǡͳ͸ͶȐǤ ††‹–‹‘ƒŽ Ž‹‹ ƒŽ •›’–‘• ‹ Ž—†‡ ‘˜‡”™‡‹‰Š–ǡ —• Ž‡ ’ƒ‹ǡ —• Ž‡ ˆƒ–‹‰—‡ǡ ƒ Ž‘™‡”‡† ‡š‡” ‹•‡ –‘Ž‡”ƒ ‡ǡ Š‡’ƒ–‘‡‰ƒŽ›ǡ –‡’‡”ƒ–—”‡ ‹•–ƒ„‹Ž‹–›ǡ Š›’‘–Š‡”‹ƒǡ †”‘™•‹‡•• ‘” Ž‡–Šƒ”‰› –Šƒ– ƒ› †‡˜‡Ž‘’ ‹–‘ ‘ƒ ‘” ‡˜‡ •—††‡ †‡ƒ–Š ȏͳ͵Ͳǡͳ͵ͳǡͳ͸ͷȐǤ ‹‘ Š‡‹ ƒŽŽ›ǡ  ‹• Šƒ”ƒ –‡”‹œ‡† „› ƒ ——Žƒ–‹‘ ‘ˆ †‹ ƒ”„‘š›Ž‹  ƒ ‹†•ǡ ƒ ›ŽǦ‰Ž› ‹‡• ƒ† ƒ ›ŽǦ ƒ”‹–‹‡• ‘ˆ ƒ”„‘Ǧ Šƒ‹ Ž‡‰–Š ͸ǦͳͲ ƒ† ƒ Š‹‰Š‡” ”ƒ–‹‘ ‘ˆ ͺ ‘˜‡” ͳͲ Šƒ‹• ‹ ’Žƒ•ƒ ƒ† —”‹‡ ȏͳ͸ͷǡͳ͹Ͳǡͳ͹͸Ȃͳͺ͵ȐǤ‹†‹˜‹†—ƒŽ•™‹–Šƒ”‡•‹†—ƒŽƒ –‹˜‹–›Š‹‰Š‡”–ŠƒͳͲΨ‘ˆ ‘–”‘Ž• •Š‘™‡† ƒ ‹Ž†‡” „‹‘ Š‡‹ ƒŽ ƒ† Ž‹‹ ƒŽ ’Š‡‘–›’‡ ȏͳ͵ͶȐǤ ‘™‡˜‡”ǡ ‘– ƒŽŽ ˜ƒ”‹ƒ„‹Ž‹–›„‡–™‡‡‹†‹˜‹†—ƒŽ• ƒ„‡‡š’Žƒ‹‡†„›”‡•‹†—ƒŽ‡œ›‡ƒ –‹˜‹–›Ǥ˜‡ƒ•—„•‡–. ʹͳ.

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