PMID- 32151767 OWN - NLM STAT- MEDLINE DCOM- 20201022 LR - 20211204 IS - 1879-2618 (Electronic) IS - 1388-1981 (Linking) VI - 1865 IP - 7 DP - 2020 Jul TI - ANGPTL3 deficiency alters the lipid profile and metabolism of cultured hepatocytes and human lipoproteins. PG - 158679 LID - S1388-1981(20)30071-8 [pii] LID - 10.1016/j.bbalip.2020.158679 [doi] AB - Loss-of-function (LOF) mutations in ANGPTL3, an inhibitor of lipoprotein lipase (LPL), cause a drastic reduction of serum lipoproteins and protect against the development of atherosclerotic cardiovascular disease. Therefore, ANGPTL3 is a promising therapy target. We characterized the impacts of ANGPTL3 depletion on the immortalized human hepatocyte (IHH) transcriptome, lipidome and human plasma lipoprotein lipidome. The transcriptome of ANGPTL3 knock-down (KD) cells showed altered expression of several pathways related to lipid metabolism. Accordingly, ANGPTL3 depleted IHH displayed changes in cellular overall fatty acid (FA) composition and in the lipid species composition of several lipid classes, characterized by abundant n-6 and n-3 polyunsaturated FAs (PUFAs). This PUFA increase coincided with an elevation of lipid mediators, among which there were species relevant for resolution of inflammation, protection from lipotoxic and hypoxia-induced ER stress, hepatic steatosis and insulin resistance or for the recovery from cardiovascular events. Cholesterol esters were markedly reduced in ANGPTL3 KD IHH, coinciding with suppression of the SOAT1 mRNA and protein. ANGPTL3 LOF caused alterations in plasma lipoprotein FA and lipid species composition. All lipoprotein fractions of the ANGPTL3 LOF subjects displayed a marked drop of 18:2n-6, while several highly unsaturated triacylglycerol (TAG) species were enriched. The present work reveals distinct impacts of ANGPTL3 depletion on the hepatocellular lipidome, transcriptome and lipid mediators, as well as on the lipidome of lipoproteins isolated from plasma of ANGPTL3-deficient human subjects. It is important to consider these lipidomics and transcriptomics findings when targeting ANGPTL3 for therapy and translating it to the human context. CI - Copyright (c) 2020 Elsevier B.V. All rights reserved. FAU - Ruhanen, Hanna AU - Ruhanen H AD - Minerva Foundation Institute for Medical Research, Helsinki, Finland; Molecular and Integrative Biosciences, University of Helsinki, Helsinki, Finland; Helsinki University Lipidomics Unit (HiLIPID), Helsinki Institute for Life Science (HiLIFE), Helsinki, Finland. FAU - Haridas, P A Nidhina AU - Haridas PAN AD - Minerva Foundation Institute for Medical Research, Helsinki, Finland. FAU - Minicocci, Ilenia AU - Minicocci I AD - Department of Translational and Precision Medicine, Sapienza University of Rome, Italy. FAU - Taskinen, Juuso H AU - Taskinen JH AD - Minerva Foundation Institute for Medical Research, Helsinki, Finland. FAU - Palmas, Francesco AU - Palmas F AD - Lipid Mediator Unit, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom. FAU - di Costanzo, Alessia AU - di Costanzo A AD - Department of Translational and Precision Medicine, Sapienza University of Rome, Italy. FAU - D'Erasmo, Laura AU - D'Erasmo L AD - Department of Translational and Precision Medicine, Sapienza University of Rome, Italy. FAU - Metso, Jari AU - Metso J AD - Minerva Foundation Institute for Medical Research, Helsinki, Finland. FAU - Partanen, Jennimari AU - Partanen J AD - Minerva Foundation Institute for Medical Research, Helsinki, Finland. FAU - Dalli, Jesmond AU - Dalli J AD - Lipid Mediator Unit, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; Centre for Inflammation and Therapeutic Innovation, Queen Mary University of London, London, UK. FAU - Zhou, You AU - Zhou Y AD - Systems Immunity University Research Institute and Division of Infection & Immunity, Cardiff University, Cardiff, United Kingdom. FAU - Arca, Marcello AU - Arca M AD - Department of Translational and Precision Medicine, Sapienza University of Rome, Italy. FAU - Jauhiainen, Matti AU - Jauhiainen M AD - Minerva Foundation Institute for Medical Research, Helsinki, Finland. FAU - Kakela, Reijo AU - Kakela R AD - Molecular and Integrative Biosciences, University of Helsinki, Helsinki, Finland; Helsinki University Lipidomics Unit (HiLIPID), Helsinki Institute for Life Science (HiLIFE), Helsinki, Finland. FAU - Olkkonen, Vesa M AU - Olkkonen VM AD - Minerva Foundation Institute for Medical Research, Helsinki, Finland; Department of Anatomy, University of Helsinki, Finland. Electronic address: vesa.olkkonen@helsinki.fi. LA - eng GR - 677542/ERC_/European Research Council/International GR - 107613/Z/15/Z/WT_/Wellcome Trust/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200306 PL - Netherlands TA - Biochim Biophys Acta Mol Cell Biol Lipids JT - Biochimica et biophysica acta. Molecular and cell biology of lipids JID - 101731727 RN - 0 (ANGPTL3 protein, human) RN - 0 (Angiopoietin-Like Protein 3) RN - 0 (Angiopoietin-like Proteins) RN - 0 (Lipoproteins) RN - 0 (Triglycerides) SB - IM MH - Adult MH - Aged MH - Angiopoietin-Like Protein 3 MH - Angiopoietin-like Proteins/genetics/*metabolism MH - Cell Line MH - Female MH - Hepatocytes/*metabolism MH - Humans MH - *Lipid Metabolism MH - Lipoproteins/blood/*metabolism MH - *Loss of Function Mutation MH - Male MH - Middle Aged MH - Triglycerides/metabolism OTO - NOTNLM OT - Angiopoietin like 3 OT - Cholesterol ester OT - Lipid metabolism OT - Lipidomics OT - Lipoprotein lipase OT - Polyunsaturated fatty acid COIS- Declaration of competing interest Authors declare no conflict of interest. EDAT- 2020/03/11 06:00 MHDA- 2020/10/23 06:00 CRDT- 2020/03/11 06:00 PHST- 2020/01/27 00:00 [received] PHST- 2020/02/28 00:00 [revised] PHST- 2020/03/04 00:00 [accepted] PHST- 2020/03/11 06:00 [pubmed] PHST- 2020/10/23 06:00 [medline] PHST- 2020/03/11 06:00 [entrez] AID - S1388-1981(20)30071-8 [pii] AID - 10.1016/j.bbalip.2020.158679 [doi] PST - ppublish SO - Biochim Biophys Acta Mol Cell Biol Lipids. 2020 Jul;1865(7):158679. doi: 10.1016/j.bbalip.2020.158679. Epub 2020 Mar 6.