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

Research output: Contribution to journalArticle

Abstract

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.

Details

Authors
  • Panu K. Luukkonen
  • Auli Nick
  • Maarit Hölttä-Vuori
  • Christoph Thiele
  • Elina Isokuortti
  • Susanna Lallukka-Brück
  • You Zhou
  • Antti Hakkarainen
  • Nina Lundbom
  • Markku Peltonen
  • Marju Orho-Melander
  • Matej Orešič
  • Tuulia Hyötyläinen
  • Leanne Hodson
  • Elina Ikonen
  • Hannele Yki-Järvinen
Organisations
External organisations
  • Minerva Foundation Institute for Medical Research
  • University of Helsinki
  • University of Bonn
  • Cardiff University
  • Helsinki University Central Hospital
  • Helsinki University of Technology
  • Finnish National Institute for Health and Welfare
  • University of Turku
  • Örebro University
  • Åbo Akademi University
  • University of Oxford
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology
Original languageEnglish
Article numbere127902
JournalJCI Insight
Volume4
Issue number16
Publication statusPublished - 2019 Aug 22
Publication categoryResearch
Peer-reviewedYes