ANGPTL3 deficiency alters the lipid profile and metabolism of cultured hepatocytes and human lipoproteins

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Ruhanen , H , Haridas , P A N , Minicocci , I , Taskinen , J H , Palmas , F , di Costanzo , A , D'Erasmo , L , Metso , J , Partanen , J , Dalli , J , Zhou , Y , Arca , M , Jauhiainen , M , Käkelä , R & Olkkonen , V M 2020 , ' ANGPTL3 deficiency alters the lipid profile and metabolism of cultured hepatocytes and human lipoproteins ' , Biochimica and Biophysica Acta. Molecular and Cell Biology of Lipids , vol. 1865 , no. 7 , 158679 . https://doi.org/10.1016/j.bbalip.2020.158679

Title: ANGPTL3 deficiency alters the lipid profile and metabolism of cultured hepatocytes and human lipoproteins
Author: Ruhanen, Hanna; Haridas, P. A. Nidhina; Minicocci, Ilenia; Taskinen, Juuso H.; Palmas, Francesco; di Costanzo, Alessia; D'Erasmo, Laura; Metso, Jari; Partanen, Jennimari; Dalli, Jesmond; Zhou, You; Arca, Marcello; Jauhiainen, Matti; Käkelä, Reijo; Olkkonen, Vesa M.
Contributor organization: Molecular and Integrative Biosciences Research Programme
Functional Lipidomics Group
Helsinki Institute of Life Science HiLIFE, Joint Activities
Medicum
Biosciences
Department of Anatomy
Date: 2020-07
Language: eng
Number of pages: 11
Belongs to series: Biochimica and Biophysica Acta. Molecular and Cell Biology of Lipids
ISSN: 1388-1981
DOI: https://doi.org/10.1016/j.bbalip.2020.158679
URI: http://hdl.handle.net/10138/332411
Abstract: 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.
Subject: Angiopoietin like 3
Lipoprotein lipase
Lipidomics
Lipid metabolism
Cholesterol ester
Polyunsaturated fatty acid
LECITHIN-CHOLESTEROL ACYLTRANSFERASE
FAMILIAL COMBINED HYPOLIPIDEMIA
ANGIOPOIETIN-LIKE PROTEIN-3
ACYL-CHAIN SPECIFICITY
APOLIPOPROTEIN C-II
TRIGLYCERIDE CLEARANCE
SUBSTRATE-SPECIFICITY
PHOSPHOLIPASE A(2)
PLASMA-LIPIDS
LIPASE
1182 Biochemistry, cell and molecular biology
116 Chemical sciences
Peer reviewed: Yes
Rights: cc_by_nc_nd
Usage restriction: openAccess
Self-archived version: acceptedVersion


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