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Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids

Luukkonen, Panu K. (author)
Minerva Foundation Institute for Medical Research, Helsinki, Finland; Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Nick, Auli (author)
Minerva Foundation Institute for Medical Research, Helsinki, Finland; Faculty of Medicine, Department of Anatomy, University of Helsinki, Helsinki, Finland
Hölttä-Vuori, Maarit (author)
Minerva Foundation Institute for Medical Research, Helsinki, Finland; Faculty of Medicine, Department of Anatomy, University of Helsinki, Helsinki, Finland
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Thiele, Christoph (author)
LIMES Institute, Bonn University, Bonn, Germany,University of Bonn
Isokuortti, Elina (author)
Minerva Foundation Institute for Medical Research, Helsinki, Finland; Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Lallukka-Brück, Susanna (author)
Minerva Foundation Institute for Medical Research, Helsinki, Finland; Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Zhou, You (author)
Minerva Foundation Institute for Medical Research, Helsinki, Finland; Systems Immunity Research Institute, Cardiff University, Cardiff, United Kingdom; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom
Hakkarainen, Antti (author)
Department of Radiology, HUS Medical Imaging Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Department of Neuroscience and Biomedical Engineering, Aalto University School of Science, Espoo, Finland.9Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland,Helsinki University of Technology,Finnish National Institute for Health and Welfare,Helsinki University Central Hospital
Lundbom, Nina (author)
Department of Radiology, HUS Medical Imaging Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland,Helsinki University Central Hospital
Peltonen, Markku (author)
Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland,Finnish National Institute for Health and Welfare
Orho-Melander, Marju (author)
Lund University,Lunds universitet,Diabetes - kardiovaskulär sjukdom,Forskargrupper vid Lunds universitet,Diabetes - Cardiovascular Disease,Lund University Research Groups
Oresic, Matej, 1967- (author)
Örebro University,Örebro universitet,Institutionen för medicinska vetenskaper,Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland
Hyötyläinen, Tuulia, 1971- (author)
Örebro University,Örebro universitet,Institutionen för naturvetenskap och teknik
Hodson, Leanne (author)
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
Ikonen, Elina (author)
Minerva Foundation Institute for Medical Research, Helsinki, Finland; Faculty of Medicine, Department of Anatomy, University of Helsinki, Helsinki, Finland
Yki-Järvinen, Hannele (author)
Minerva Foundation Institute for Medical Research, Helsinki, Finland; Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland,Helsinki University Central Hospital
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 (creator_code:org_t)
2019-08-22
2019
English.
In: JCI Insight. - : American Society for Clinical Investigation (ASCI). - 2379-3708. ; 4:16
Related links:
http://insight.jci.o...
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http://dx.doi.org/10...
https://urn.kb.se/re...
https://doi.org/10.1...
https://lup.lub.lu.s...
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • The common patatin-like phospholipase domain-containing protein 3 (PNPLA3) variant I148M predisposes to nonalcoholic liver disease but not its metabolic sequelae. We compared the handling of labeled polyunsaturated fatty acids (PUFAs) and saturated fatty acids (SFA) in vivo in humans and in cells harboring different PNPLA3 genotypes. In 148M homozygous individuals, triglycerides (TGs) in very low-density lipoproteins (VLDL) were depleted of PUFAs both under fasting and postprandial conditions compared with 148I homozygotes, and the PUFA/SFA ratio in VLDL-TGs was lower relative to the chylomicron precursor pool. In human PNPLA3-148M and PNPLA3-KO cells, PUFA but not SFA incorporation into TGs was increased at the expense of phosphatidylcholines, and under lipolytic conditions, PUFA-containing diacylglycerols (DAGs) accumulated compared with PNPLA3-148I cells. Polyunsaturated TGs were increased, while phosphatidylcholines (PCs) were decreased in the human liver in 148M homozygous individuals as compared with 148I homozygotes. We conclude that human PNPLA3-I148M is a loss-of-function allele that remodels liver TGs in a polyunsaturated direction by impairing hydrolysis/transacylation of PUFAs from DAGs to feed phosphatidylcholine synthesis.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Physiology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Keyword

Genetic variation
Hepatitis
Hepatology
Metabolism

Publication and Content Type

ref (subject category)
art (subject category)

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