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Ritonavir impairs lipoprotein lipase-mediated lipolysis and decreases uptake of fatty acids in adipose tissue

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Author: Boer, M.A.M. den · Berbée, J.F.P. · Reiss, P. · Valk, M. van der · Voshol, P.J. · Kuipers, F. · Havekes, L.M. · Rensen, P.C.N. · Romijn, J.A.
Type:article
Date:2006
Institution: Gaubius Instituut TNO
Source:Arteriosclerosis, Thrombosis, and Vascular Biology, 1, 26, 124-129
Identifier: 239070
doi: doi10.1161/01.ATV.0000194073.87647.10
Keywords: Dyslipidemia · FA metabolism · Protease inhibitor · TG metabolism · Transgenic mice · Albumin · Lipoprotein lipase · Proteinase inhibitor · Ritonavir · Triacylglycerol · Triolein · Very low density lipoprotein · Anticoagulant agent · Apolipoprotein E · Apolipoprotein E3 (Leidein) · Diagnostic agent · Fatty acid · Heparin · Tritium · Very low density lipoprotein cholesterol · Adipose tissue · Animal tissue · Clearance · Controlled study · Drug mechanism · Emulsion · Enzyme activity · Fat intake · Fatty acid metabolism · Fatty acid transport · Half life time · Hypertriglyceridemia · Lipid diet · Lipodystrophy · Lipolysis · Mouse · Nonhuman · Postprandial state · Transgenic mouse · Triacylglycerol blood level · Biosynthesis · Blood · Chemically induced disorder · Drug effect · Enzyme activation · Genetics · Human immunodeficiency virus infection · Metabolism · Adipose Tissue · Animals · Anticoagulants · Apolipoprotein E3 · Apolipoproteins E · Cholesterol, VLDL · Emulsions · Enzyme Activation · Fatty Acids · Female · Heparin · HIV Infections · HIV Protease Inhibitors · Hypertriglyceridemia · Lipolysis · Lipoprotein Lipase · Mice · Mice, Transgenic · Postprandial Period · Ritonavir · Triglycerides · Triolein · Tritium

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 3.1.1.34; Ritonavir; Triglycerides; Triolein, 122-32-7; Tritium, 10028-17-8