TY - JOUR T1 - Comprehensive lipidomics reveals reduced hepatic lipid turnover in NAFLD during alcohol intoxication JF - medRxiv DO - 10.1101/2021.02.18.21251910 SP - 2021.02.18.21251910 AU - Israelsen, Mads AU - Kim, Min AU - Suvitaival, Tommi AU - Stæhr Madsen, Bjørn AU - Hansen, Camilla Dalby AU - Torp, Nikolaj AU - Trost, Kajetan AU - Thiele, Maja AU - Hansen, Torben AU - Legido-Quigley, Cristina AU - Krag, Aleksander AU - , Y1 - 2021/01/01 UR - http://medrxiv.org/content/early/2021/02/19/2021.02.18.21251910.abstract N2 - Background &amp; Aims In experimental models, alcohol induces acute changes in lipid metabolism that cause hepatocyte lipoapoptosis and inflammation. Here we study human hepatic lipid turnover during controlled alcohol intoxication.Methods We studied 39 participants with three distinct hepatic phenotypes: alcohol-related liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), and healthy controls. Alcohol was administrated via nasogastric tube over 30 minutes. Hepatic and systemic venous blood were sampled simultaneously at three time points: baseline, 60 and 180 min after alcohol intervention. Liver biopsies were sampled 240 minutes after alcohol intervention. We used ultra-high-performance liquid chromatograph mass spectrometry to measure levels of more than 250 lipid species from the blood and liver samples.Results After alcohol intervention, the levels of blood free fatty acid (FFA) and lysophosphatidylcholine (LPC) decreased while triglyceride (TG) increased. FFA was the only lipid class to decrease in NAFLD after alcohol intervention, while LPC and FFA decreased and TG increased after intervention in ALD and healthy controls. Fatty acid chain uptake preference in FFAs and LPCs were oleic acid, linoleic acid, arachidonic acid, and docosahexaenoic acid. Hepatic venous blood FFA and LPC levels were lower when compared to systemic venous blood levels throughout the intervention. After alcohol intoxication, liver lipidome in ALD was similar to that in NAFLD.Conclusions Alcohol intoxication induces rapid changes in circulating lipids including hepatic turnaround from FFA and LPC, potentially leading to lipoapoptosis and steatohepatitis. TG clearance was suppressed in NAFLD, possibly explaining why alcohol and NAFLD are synergistic risk factors for disease progression. These effects may be central to the pathogenesis of ALD.Competing Interest StatementThe authors have declared no competing interest.Clinical TrialNCT03018990Funding StatementGrant support Challenge Grant MicrobLiver, NNF15OC0016692, Novo Nordisk Foundation. Conflicts of interests All authors declare no conflicts of interests. Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The study was approved by the Ethical Committee of Southern Denmark (ID: S-20160083)All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAnonymised data on request.ALDalcohol-related liver diseaseALTalanine aminotransferaseANOVAanalysis of varianceASTasparagine aminotransferaseBMIbody mass indexCerceramideCTLhealthy controlDGdiglycerideFFAfree fatty acidGGTgamma-glutamyl transferaseHbA1chemoglobin A1cHDLhigh-density lipoproteinHexCerhexosylceramideHOMA-IRHomeostatic Model Assessment of Insulin ResistanceIQRinterquartile rangeLacCerlactosylceramidesLCATlecithin:cholesterol acyltransferaseLPClysophosphatidylcholineLPElysophosphatidylethanolamineINRinternational normalized ratioLDLlow-density lipoproteinNAFLDnon-alcoholic fatty liver diseasePCphosphatidylcholinePEphosphatidylethanolamineP-glucoseplasma glucosePIphosphatidylinositolPLA2phospholipase A2QCquality controlSDstandard deviationSHexCersulfatides hexosylceramideSMsphingomyelinTEtransient elastographyTGtriglyceride ER -