Print Email Facebook Twitter Ritonavir impairs lipoprotein lipase-mediated lipolysis and decreases uptake of fatty acids in adipose tissue Title Ritonavir impairs lipoprotein lipase-mediated lipolysis and decreases uptake of fatty acids in adipose tissue Author den Boer, M.A.M. Berbée, J.F.P. Reiss, P. van der Valk, M. Voshol, P.J. Kuipers, F. Havekes, L.M. Rensen, P.C.N. Romijn, J.A. Gaubius Instituut TNO Publication year 2006 Abstract Objective - The use of the HIV protease inhibitor ritonavir (RTV) is frequently associated with hypertriglyceridemia and lipodystrophy. The aim of our study was to determine the mechanism underlying the observed hypertriglyceridemia. Methods and Results - Feeding female APOE*3-Leiden transgenic mice a Western-type diet supplemented with RTV (35 mg/kg per day) for 2 weeks resulted in a 2-fold increase in fasting plasma triglyceride (TG) levels, which was specific for very low-density lipoprotein (VLDL). RTV did not change the hepatic VLDL-TG production. Instead, RTV did increase the postprandial TG response to an oral fat load (area under the curve, 25.5±12.1 versus 13.8±6.8 mmol/L per hour in controls; P<0.05). Likewise, RTV hampered the plasma clearance of intravenously injected glycerol tri[3H]oleate-labeled VLDL-like emulsion particles (half time, 19.3±10.5 versus 5.0±1.3 minutes in controls; P<0.05) associated with a decrease of 44% in plasma lipoprotein lipase activity. Accordingly, RTV decreased the uptake of TG-derived fatty acids (FAs) into adipose tissue, as well as the uptake of albumin-bound FA. Conclusions - We conclude that RTV causes hypertriglyceridemia via decreased lipoprotein lipase-mediated clearance of VLDL-TG. In addition, RTV specifically impairs the uptake of FA in adipose tissue, which may contribute to the lipodystrophy that is frequently observed in HIV-infected subjects on antiretroviral therapy. © 2005 American Heart Association, Inc. Chemicals / CAS: lipoprotein lipase, 83137-80-8, 9004-02-8; proteinase inhibitor, 37205-61-1; ritonavir, 155213-67-5; triolein, 122-32-7; heparin, 37187-54-5, 8057-48-5, 8065-01-8, 9005-48-5; tritium, 10028-17-8; Anticoagulants; apolipoprotein E3 (Leidein); Apolipoprotein E3; Apolipoproteins E; Cholesterol, VLDL; Emulsions; Fatty Acids; Heparin, 9005-49-6; HIV Protease Inhibitors; Lipoprotein Lipase, EC 188.8.131.52; Ritonavir; Triglycerides; Triolein, 122-32-7; Tritium, 10028-17-8 Subject DyslipidemiaFA metabolismProtease inhibitorTG metabolismTransgenic miceAlbuminLipoprotein lipaseProteinase inhibitorRitonavirTriacylglycerolTrioleinVery low density lipoproteinAnticoagulant agentApolipoprotein EApolipoprotein E3 (Leidein)Diagnostic agentFatty acidHeparinTritiumVery low density lipoprotein cholesterolAdipose tissueAnimal tissueClearanceControlled studyDrug mechanismEmulsionEnzyme activityFat intakeFatty acid metabolismFatty acid transportHalf life timeHypertriglyceridemiaLipid dietLipodystrophyLipolysisMouseNonhumanPostprandial stateTransgenic mouseTriacylglycerol blood levelBiosynthesisBloodChemically induced disorderDrug effectEnzyme activationGeneticsHuman immunodeficiency virus infectionMetabolismAdipose TissueAnimalsAnticoagulantsApolipoprotein E3Apolipoproteins ECholesterol, VLDLEmulsionsEnzyme ActivationFatty AcidsFemaleHeparinHIV InfectionsHIV Protease InhibitorsHypertriglyceridemiaLipolysisLipoprotein LipaseMiceMice, TransgenicPostprandial PeriodRitonavirTriglyceridesTrioleinTritium To reference this document use: http://resolver.tudelft.nl/uuid:ae09e748-d56e-4eeb-b9cf-21d64b8abb93 DOI https://doi.org/10.1161/01.atv.0000194073.87647.10 TNO identifier 239070 ISSN 1079-5642 Source Arteriosclerosis, Thrombosis, and Vascular Biology, 26 (1), 124-129 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.