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Original research
LPIAT1/MBOAT7 depletion increases triglyceride synthesis fueled by high phosphatidylinositol turnover
  1. Yuki Tanaka1,
  2. Yuta Shimanaka1,
  3. Andrea Caddeo2,
  4. Takuya Kubo1,
  5. Yanli Mao1,
  6. Tetsuya Kubota3,
  7. Naoto Kubota4,5,
  8. Toshimasa Yamauchi4,
  9. Rosellina Margherita Mancina2,
  10. Guido Baselli6,7,
  11. Panu Luukkonen8,9,10,
  12. Jussi Pihlajamäki11,12,
  13. Hannele Yki-Järvinen8,9,
  14. Luca Valenti6,7,
  15. Hiroyuki Arai1,13,14,
  16. Stefano Romeo2,15,16,
  17. Nozomu Kono1
  1. 1Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
  2. 2Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
  3. 3Division of Diabetes and Metabolism, The Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan
  4. 4Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  5. 5Department of Clinical Nutrition Therapy, The University of Tokyo Hospital, The University of Tokyo, Tokyo, Japan
  6. 6Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy
  7. 7Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
  8. 8Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
  9. 9Minerva Foundation Institute for Medical Research, Helsinki, Finland
  10. 10Department of Internal Medicine, Yale University, New Haven, CT, USA, Yale University, New Haven, Connecticut, USA
  11. 11Department of Clinical Nutrition, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
  12. 12Clinical Nutrition and Obesity Center, Kuopio University Hospital, Kuopio, Finland
  13. 13AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, Japan
  14. 14Present address: Laboratory of Microenvironmental and Metabolic Health Science, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  15. 15Clinical Nutrition Unit, Department of Medical and Surgical Science, Magna Graecia University, Catanzaro, Italy
  16. 16Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden
  1. Correspondence to Dr Nozomu Kono, The University of Tokyo, Bunkyo-ku 113-0033, Japan; nozomu{at}mol.f.u-tokyo.ac.jp; Dr Stefano Romeo, Department of Clinical and Molecular Medicine, University of Gothenburg Sahlgrenska Academy, Gothenburg, Sweden; stefano.romeo{at}wlab.gu.se

Abstract

Objective Non-alcoholic fatty liver disease (NAFLD) is a common prelude to cirrhosis and hepatocellular carcinoma. The genetic rs641738 C>T variant in the lysophosphatidylinositol acyltransferase 1 (LPIAT1)/membrane bound O-acyltransferase domain-containing 7, which incorporates arachidonic acid into phosphatidylinositol (PI), is associated with the entire spectrum of NAFLD. In this study, we investigated the mechanism underlying this association in mice and cultured human hepatocytes.

Design We generated the hepatocyte-specific Lpiat1 knockout mice to investigate the function of Lpiat1 in vivo. We also depleted LPIAT1 in cultured human hepatic cells using CRISPR-Cas9 systems or siRNA. The effect of LPIAT1-depletion on liver fibrosis was examined in mice fed high fat diet and in liver spheroids. Lipid species were measured using liquid chromatography-electrospray ionisation mass spectrometry. Lipid metabolism was analysed using radiolabeled glycerol or fatty acids.

Results The hepatocyte-specific Lpiat1 knockout mice developed hepatic steatosis spontaneously, and hepatic fibrosis on high fat diet feeding. Depletion of LPIAT1 in cultured hepatic cells and in spheroids caused triglyceride accumulation and collagen deposition. The increase in hepatocyte fat content was due to a higher triglyceride synthesis fueled by a non-canonical pathway. Indeed, reduction in the PI acyl chain remodelling caused a high PI turnover, by stimulating at the same time PI synthesis and breakdown. The degradation of PI was mediated by a phospholipase C, which produces diacylglycerol, a precursor of triglyceride.

Conclusion We found a novel pathway fueling triglyceride synthesis in hepatocytes, by a direct metabolic flow of PI into triglycerides. Our findings provide an insight into the pathogenesis and therapeutics of NAFLD.

  • fatty liver
  • hepatic fibrosis
  • lipids
  • lipid metabolism
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Footnotes

  • YT, YS and AC are joint first authors.

  • SR and NK are joint senior authors.

  • Twitter @lucavalenti75

  • Contributors YT, YS and AC designed and performed the experiments, analysed the data, interpreted the results and wrote the manuscript. TK performed the lipid analysis and interpreted the results. YM performed biochemical and histological studies. TK, TY and NK performed oxygen consumption experiments. RMM analysed the data and interpreted the results from lipidomic and transcriptomic data in human liver; GB and LV contributed to transcriptomic data generation, analysis and interpretation in human liver; PL and HA contributed to lipidomic data generation, analysis and interpretation in human liver; JP contributed to lipidomic data interpretation in human liver; HA, SR and NK designed the experiments, interpreted the results and wrote the manuscript.

  • Funding This work was supported by Grants-in-Aid for Scientific Research (S) (grant numbers 23 227 004 and 17H06164 to HA) and for Scientific Research on Innovative Areas (17H06418 to HA); by AMED-CREST, AMED (JP 18gm0710002 to HA); by the Swedish Research Council (Vetenskapsrådet (VR), 2016–01527 to SR); by the Swedish state under the Agreement between the Swedish government and the county councils (the ALF-agreement) (SU 2018–04276 to SR); by the Novonordisk Foundation Grant for Excellence in Endocrinology (Excellence Project, 9321–430 to SR); by Wallenberg Academy Fellows from the Knut and Alice Wallenberg Foundation (KAW 2017.0203 to SR); by the Novonordisk Project grants in Endocrinology and Metabolism (SR); by Astra Zeneca Agreement for Research (SR); by Grant SSF ITM17-0384, Swedish Foundation for Strategic Research (SR) and by the Novo Nordisk and Sigrid Jusélius Foundations (PL).

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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