{"id":848,"date":"2023-12-12T12:39:36","date_gmt":"2023-12-12T12:39:36","guid":{"rendered":"https:\/\/dev.minervainstitute.fi\/fettleversjukdom-och-diabetes\/"},"modified":"2024-01-20T19:53:39","modified_gmt":"2024-01-20T19:53:39","slug":"fettleversjukdom-och-diabetes","status":"publish","type":"page","link":"https:\/\/minervainstitute.fi\/sv\/forskningsgrupper\/fettleversjukdom-och-diabetes\/","title":{"rendered":"Fettleversjukdom och diabetes"},"content":{"rendered":"

Fettleversjukdom och diabetes<\/h1>\n<\/div>
<\/div><\/div>

Huvudm\u00e5let \u00e4r att studera patogenesen vid fettleversjukdom och diabetes hos m\u00e4nniskor med s\u00e4rskilt fokus p\u00e5 rollen av den mitokondriella metabolismen i levern.<\/p>\n

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Icke-alkoholisk fettleversjukdom (NAFLD) \u00e4r heterogen. ”Metabolisk” NAFLD f\u00f6ruts\u00e4ger b\u00e5de avancerad leversjukdom och metabolisk (typ 2-diabetes) sjukdom, medan vanliga genetiska former som kan h\u00e4nf\u00f6ras till varianter i PNPLA3, TM6SF2 och MBOAT7 endast predisponerar leversjukdomar. Vi har nyligen visat att de patogena mekanismerna bakom de metaboliska och genetiska komponenterna i NAFLD \u00e4r fundamentalt olika. Den metaboliska komponenten k\u00e4nnetecknas av substrat\u00f6verskott och \u00f6kade niv\u00e5er av fettv\u00e4vnadslipogenes och hepatisk de novo lipogenes (DNL)<\/span>. D\u00e4remot k\u00e4nnetecknas inte den genetiska komponenten av detta, utan leder ist\u00e4llet till ett \u00f6kat levermitokondriellt redoxtillst\u00e5nd, en mark\u00f6r f\u00f6r mitokondriell dysfunktion. <\/span> <\/p>\n<\/div>\n

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<\/span>Helt nyligen visade vi att PNPLA3-varianten paradoxalt nog minskar lever-DNL, vilket var associerat med en minskad hastighet i det mitokondriella citratsyntasfl\u00f6det i levern, dvs. det hastighetsbegr\u00e4nsande steget i TCA-cykeln som ocks\u00e5 ger citrat f\u00f6r DNL. D\u00e4remot \u00f6kade ketogenesen ,eftersom acetyl-CoA som bildades under fettsyreoxidationen inte kunde ta sig in i TCA-cykeln. Tillsammans visar dessa data att PNPLA3-varianten, som \u00e4r den starkaste genetiska riskfaktorn f\u00f6r NAFLD, inducerar levermitokondriell dysfunktion. Dessa fynd har implikationer i behandlingen av NAFLD. DNL-h\u00e4mmare kan vara skadliga i PNPLA3-variantb\u00e4rare, medan farmakoterapier som stimulerar den levermitokondriella funktionen, s\u00e5som sk\u00f6ldk\u00f6rtelns hormonreceptoragonister eller de mitokondriella frikopplarna kan utg\u00f6ra ett logiskt behandlingsalternativ f\u00f6r dessa patienter. <\/p>\n<\/div>\n

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Vi utf\u00f6r kliniska studier p\u00e5 m\u00e4nniskor d\u00e4r vi kombinerar nya stabila isotopmetoder, metabolomik och genetik f\u00f6r att unders\u00f6ka patogenesen hos fettleversjukdomar och diabetes. Dessutom anv\u00e4nder vi oss av en vertikal forskningsmetod genom att kombinera analyser av storskaliga datam\u00e4ngder f\u00f6r att validera v\u00e5ra hypoteser p\u00e5 populationsniv\u00e5 med mus- och in vitro-experiment f\u00f6r att belysa de underliggande molekyl\u00e4ra mekanismerna. <\/span><\/p>\n<\/div>\n<\/div><\/div><\/div>

<\/span><\/div>

Gruppledare<\/h3>\n

Panu Luukkonen, MD, docent
\npanu.luukkonen@helsinki.fi<\/p>\n<\/div>

Gruppmedlemmar<\/h3>\n

Hannele Yki-J\u00e4rvinen, MD, FRCP, professor
\nKimmo Porthan, MD
\nLaura Gran\u00f6, MD
\nSirkku J\u00e4ntti, FD
\nMari Lahelma, MD
\nP.A. Nidhina Haridas, PhD
\nNoora Ahlholm, ML
\nSami Qadri, ML
\nRiikka Sane, ML
\nMari Jokinen, FM
\nJuho Asteljoki, FK
\nNova Hongisto, FK
\nAnni Poikola, medicinstudent
\nDaniel Segercrantz, medicinstudent
\nAila Karioja-Kallio, torskningssjuksj\u00f6terska
\nP\u00e4ivi Ihamuotila, torskningssjuksj\u00f6terska<\/p>\n<\/div><\/div><\/div>

<\/div><\/div><\/div>
<\/span><\/div>

Gruppledare<\/h3>\n

Panu Luukkonen, MD, docent
\npanu.luukkonen@helsinki.fi<\/p>\n<\/div>

Gruppmedlemmar<\/h3>\n

Hannele Yki-J\u00e4rvinen, MD, FRCP, professor
\nKimmo Porthan, MD
\nLaura Gran\u00f6, MD
\nSirkku J\u00e4ntti, FD
\nMari Lahelma, MD
\nP.A. Nidhina Haridas, PhD
\nNoora Ahlholm, ML
\nSami Qadri, ML
\nRiikka Sane, ML
\nMari Jokinen, FM
\nJuho Asteljoki, FK
\nNova Hongisto, FK
\nAnni Poikola, medicinstudent
\nDaniel Segercrantz, medicinstudent
\nAila Karioja-Kallio, torskningssjuksj\u00f6terska
\nP\u00e4ivi Ihamuotila, torskningssjuksj\u00f6terska<\/p>\n<\/div><\/div><\/div><\/div><\/div>

Utvalda publikationer<\/h3>\n<\/div>
<\/div><\/div>

Luukkonen PK, Porthan K, Ahlholm N, Rosqvist F, Dufour S, Zhang XM, Lehtim\u00e4ki TE, Sepp\u00e4nen W, Orho-Melander M, Hodson L, Petersen KF, Shulman GI, Yki-J\u00e4rvinen H. The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans. Cell Metab. 2023:S1550-4131(23)00377-7.<\/p>\n

Luukkonen PK, Sakuma I, Gaspar RC, Mooring M, Nasiri A, Kahn M, Zhang XM, Zhang D, Sammalkorpi H, Penttil\u00e4 AK, Orho-Melander M, Arola J, Juuti A, Zhang X, Yimlamai D, Yki-J\u00e4rvinen H, Petersen KF, Shulman GI. Inhibition of HSD17B13 protects against liver fibrosis by inhibition of pyrimidine catabolism in nonalcoholic steatohepatitis. Proc Natl Acad Sci U S A. 2023;120(4):e2217543120.<\/p>\n

Tamaki N*, Ahlholm N*, Luukkonen PK, Porthan K, Sharpton SR, Ajmera V, Kono Y, Dave S, Ahmed A, Sundaram V, Wilkinson MJ, Patton H, Gupta H, Cervantes V, Hernandez C, Lopez SJ, Loomba R, Baumgartner A, Richards L, Arkkila PE, Nemes K, Isoniemi H, Yki-J\u00e4rvinen H, Loomba R. Risk of advanced fibrosis in first-degree relatives of patients with nonalcoholic fatty liver disease. J Clin Invest. 2022;132(21):e162513.<\/p>\n

Luukkonen PK, Qadri S, Ahlholm N, Porthan K, M\u00e4nnist\u00f6 V, Sammalkorpi H, Penttil\u00e4 AK, Hakkarainen A, Lehtim\u00e4ki TE, Gaggini M, Gastaldelli A, Ala-Korpela M, Orho-Melander M, Arola J, Juuti A, Pihlajam\u00e4ki J, Hodson L, Yki-J\u00e4rvinen H. Distinct Contributions of Metabolic Dysfunction and Genetic Risk Factors in the Pathogenesis of Non-Alcoholic Fatty Liver Disease. J Hepatol. 2022;76(3):526-535.<\/p>\n

Yki-J\u00e4rvinen H, Luukkonen PK, Hodson L, Moore JB. Dietary carbohydrates and fats in NAFLD. Nat Rev Gastroenterol Hepatol. 2021;18(11):770-786.<\/p>\n

Luukkonen PK, Dufour S, Lyu K, Zhang XM, Hakkarainen A, Lehtim\u00e4ki TE, Cline GW, Petersen KF, Shulman GI*, Yki-J\u00e4rvinen H*. Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A. 2020;117(13):7347-7354.<\/p>\n

Luukkonen PK, Tukiainen T, Juuti A, Sammalkorpi H, Nidhina Haridas PA, Niemel\u00e4 O, Arola J, Orho-Melander M, Hakkarainen A, Kovanen PT, Dwivedi O, Groop L, Hodson L, Gastaldelli A, Hy\u00f6tyl\u00e4inen T, Oresic M, Yki-J\u00e4rvinen H. Hydroxysteroid 17-\u03b2 dehydrogenase increases phospholipids and protects against fibrosis in nonalcoholic fatty liver disease. JCI Insight. 2020;5(5).<\/p>\n

Luukkonen PK*, Nick A*, H\u00f6ltt\u00e4-Vuori M, Thiele C, Isokuortti E, Lallukka-Br\u00fcck S, Zhou Y, Hakkarainen A, Lundbom N, Peltonen M, Orho-Melander M, Ore\u0161i\u010d M, Hy\u00f6tyl\u00e4inen T, Hodson L, Ikonen E, Yki-J\u00e4rvinen H. Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids. JCI Insight. 2019;4(16):e127902.<\/p>\n

Luukkonen PK, S\u00e4devirta S, Zhou Y, Kayser B, Ali A, Ahonen L, Lallukka S, Pelloux V,Gaggini M, Jian C, Hakkarainen A, Lundbom N, Gylling H, Salonen A, Ore\u0161i\u010d M, Hy\u00f6tyl\u00e4inen T, Orho-Melander M, Rissanen A, Gastaldelli A, Cl\u00e9ment K, Hodson L, Yki-J\u00e4rvinen H. Saturated Fat is More Metabolically Harmful for the Human Liver than Unsaturated Fat or Simple Sugars. Diabetes Care. 2018;41(8):1732-1739.<\/p>\n

Luukkonen PK*, Zhou Y*, S\u00e4devirta S, Leivonen M, Arola J, Ore\u0161i\u010d M, Hy\u00f6tyl\u00e4inen T, Yki-J\u00e4rvinen H. Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease. J Hepatol. 2016;64:1167-75.<\/p>\n<\/div><\/div><\/div><\/div><\/div>

Finansi\u00e4rer av forskningen<\/h3>\n<\/div>
<\/div><\/div>

Finlands Akademi
\nEmil Aaltosen S\u00e4\u00e4ti\u00f6
\nEU Horizon 2020, Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS)
\nStatens forskningsfinansiering
\nSuomen L\u00e4\u00e4ketieteen S\u00e4\u00e4ti\u00f6
\nInstrumentariumin Tiedes\u00e4\u00e4ti\u00f6
\nNovo Nordisk Foundation
\nOrionin Tutkimuss\u00e4\u00e4ti\u00f6
\nSigrid Jus\u00e9lius Stiftelse
\nHelsingfors universitet<\/p>\n<\/div><\/div><\/div><\/div><\/div>

F\u00f6lja<\/h3>\n<\/div>
<\/div><\/div>

Visit the group\u2019s website at the University of Helsinki<\/a><\/p>\n<\/div><\/div><\/div><\/div><\/div><\/p>\n","protected":false},"excerpt":{"rendered":"","protected":false},"author":1,"featured_media":0,"parent":878,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"100-width.php","meta":{"footnotes":""},"class_list":["post-848","page","type-page","status-publish","hentry"],"_links":{"self":[{"href":"https:\/\/minervainstitute.fi\/sv\/wp-json\/wp\/v2\/pages\/848","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/minervainstitute.fi\/sv\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/minervainstitute.fi\/sv\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/minervainstitute.fi\/sv\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/minervainstitute.fi\/sv\/wp-json\/wp\/v2\/comments?post=848"}],"version-history":[{"count":2,"href":"https:\/\/minervainstitute.fi\/sv\/wp-json\/wp\/v2\/pages\/848\/revisions"}],"predecessor-version":[{"id":850,"href":"https:\/\/minervainstitute.fi\/sv\/wp-json\/wp\/v2\/pages\/848\/revisions\/850"}],"up":[{"embeddable":true,"href":"https:\/\/minervainstitute.fi\/sv\/wp-json\/wp\/v2\/pages\/878"}],"wp:attachment":[{"href":"https:\/\/minervainstitute.fi\/sv\/wp-json\/wp\/v2\/media?parent=848"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}