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

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Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids. / Luukkonen, Panu K.; Nick, Auli; Hölttä-Vuori, Maarit; Thiele, Christoph; Isokuortti, Elina; Lallukka-Brück, Susanna; Zhou, You; Hakkarainen, Antti; Lundbom, Nina; Peltonen, Markku; Orho-Melander, Marju; Orešič, Matej; Hyötyläinen, Tuulia; Hodson, Leanne; Ikonen, Elina; Yki-Järvinen, Hannele.

In: JCI Insight, Vol. 4, No. 16, e127902, 22.08.2019.

Research output: Contribution to journalArticle

Harvard

Luukkonen, PK, Nick, A, Hölttä-Vuori, M, Thiele, C, Isokuortti, E, Lallukka-Brück, S, Zhou, Y, Hakkarainen, A, Lundbom, N, Peltonen, M, Orho-Melander, M, Orešič, M, Hyötyläinen, T, Hodson, L, Ikonen, E & Yki-Järvinen, H 2019, 'Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids', JCI Insight, vol. 4, no. 16, e127902. https://doi.org/10.1172/jci.insight.127902

APA

Luukkonen, P. K., Nick, A., Hölttä-Vuori, M., Thiele, C., Isokuortti, E., Lallukka-Brück, S., ... Yki-Järvinen, H. (2019). Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids. JCI Insight, 4(16), [e127902]. https://doi.org/10.1172/jci.insight.127902

CBE

Luukkonen PK, Nick A, Hölttä-Vuori M, Thiele C, Isokuortti E, Lallukka-Brück S, Zhou Y, Hakkarainen A, Lundbom N, Peltonen M, Orho-Melander M, Orešič M, Hyötyläinen T, Hodson L, Ikonen E, Yki-Järvinen H. 2019. Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids. JCI Insight. 4(16). https://doi.org/10.1172/jci.insight.127902

MLA

Vancouver

Luukkonen PK, Nick A, Hölttä-Vuori M, Thiele C, Isokuortti E, Lallukka-Brück S et al. Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids. JCI Insight. 2019 Aug 22;4(16). e127902. https://doi.org/10.1172/jci.insight.127902

Author

Luukkonen, Panu K. ; Nick, Auli ; Hölttä-Vuori, Maarit ; Thiele, Christoph ; Isokuortti, Elina ; Lallukka-Brück, Susanna ; Zhou, You ; Hakkarainen, Antti ; Lundbom, Nina ; Peltonen, Markku ; Orho-Melander, Marju ; Orešič, Matej ; Hyötyläinen, Tuulia ; Hodson, Leanne ; Ikonen, Elina ; Yki-Järvinen, Hannele. / Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids. In: JCI Insight. 2019 ; Vol. 4, No. 16.

RIS

TY - JOUR

T1 - Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids

AU - Luukkonen, Panu K.

AU - Nick, Auli

AU - Hölttä-Vuori, Maarit

AU - Thiele, Christoph

AU - Isokuortti, Elina

AU - Lallukka-Brück, Susanna

AU - Zhou, You

AU - Hakkarainen, Antti

AU - Lundbom, Nina

AU - Peltonen, Markku

AU - Orho-Melander, Marju

AU - Orešič, Matej

AU - Hyötyläinen, Tuulia

AU - Hodson, Leanne

AU - Ikonen, Elina

AU - Yki-Järvinen, Hannele

PY - 2019/8/22

Y1 - 2019/8/22

N2 - 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.

AB - 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.

U2 - 10.1172/jci.insight.127902

DO - 10.1172/jci.insight.127902

M3 - Article

VL - 4

JO - JCI Insight

T2 - JCI Insight

JF - JCI Insight

SN - 2379-3708

IS - 16

M1 - e127902

ER -