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Impaired hepatic lipid synthesis from polyunsaturated fatty acids in TM6SF2 E167K variant carriers with NAFLD
Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland.
Minerva Foundation Institute for Medical Research, Helsinki, Finland; Systems Immunity University Research Institute and Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Minerva Foundation Institute for Medical Research, Helsinki, Finland.
Institute for Molecular Medicine Finland, Helsinki, Finland.
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2017 (English)In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 67, no 1, 128-136 p.Article in journal (Refereed) Published
Abstract [en]

Background: Carriers of the transmembrane 6 superfamily member 2 E167K gene variant (TM6SF2(EK/KK)) have decreased expression of the TM6SF2 gene and increased risk of NAFLD and NASH. Unlike common 'obese/metabolic' NAFLD, these subjects lack hypertriglyceridemia and have lower risk of cardiovascular disease. In animals, phosphatidylcholine (PC) deficiency results in a similar phenotype. PCs surround the core of VLDL consisting of triglycerides (TGs) and cholesteryl-esters (CEs). We determined the effect of the TM6SF2 E167K on these lipids in the human liver and serum and on hepatic gene expression and studied the effect of TM6SF2 knockdown on hepatocyte handling of these lipids.

Methods: Liver biopsies were taken from subjects characterized with respect to the TM6SF2 genotype, serum and liver lipidome, gene expression and histology. In vitro, after TM6SF2 knockdown in HuH-7 cells, we compared incorporation of different fatty acids into TGs, CEs, and PCs.

Results: The TM6SF2(EK/KK) and TM6SF2EE groups had similar age, gender, BMI and HOMA-IR. Liver TGs and CEs were higher and liver PCs lower in the TM6SF2(EK/KK) than the TM6SF2EE group (p<0.05). Polyunsaturated fatty acids (PUFA) were deficient in liver and serum TGs and liver PCs but hepatic free fatty acids were relatively enriched in PUFA (p<0.05). Incorporation of PUFA into TGs and PCs in TM6SF2 knockdown hepatocytes was decreased (p< 0.05). Hepatic expression of TM6SF2 was decreased in variant carriers, and was co-expressed with genes regulated by PUFAs.

Conclusions: Hepatic lipid synthesis from PUFAs is impaired and could contribute to deficiency in PCs and increased intrahepatic TG in TM6SF2 E167K variant carriers. (C) 2017 European Association for the Study of the Liver.

Place, publisher, year, edition, pages
Elsevier, 2017. Vol. 67, no 1, 128-136 p.
Keyword [en]
Transmembrane 6 superfamily member 2, Triglycerides, Cholesterol esters, Arachidonic acid, Phosphatidylcholines, Non-alcoholic fatty liver disease, Lipogenesis, Genotype, Hepatocytes, Fatty acids
National Category
Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:oru:diva-58776DOI: 10.1016/j.jhep.2017.02.014ISI: 000403335600018PubMedID: 28235613Scopus ID: 2-s2.0-85017448528OAI: oai:DiVA.org:oru-58776DiVA: diva2:1128576
Note

Funding Agencies:

Faculty of Medicine of the University of Helsinki  

Helsinki University Hospital  

Academy of Finland  

EU/EFPIA Innovative Medicines Initiative Joint Undertaking (EMIF)  115372 

EU  EPoS 634413 

Sigrid Juselius Foundation  

EVO Foundation  

Liv och Halsa Foundation  

Magnus Ehrnrooth Foundation  

Finnish Cardiovascular Research Foundation  

Cardiff University SIURI Seedcorn fund Foundation 

Available from: 2017-07-26 Created: 2017-07-26 Last updated: 2018-01-18Bibliographically approved

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Hyötyläinen, TuuliaOresic, Matej

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