title: Ritonavir impairs lipoprotein lipase-mediated lipolysis and decreases uptake of fatty acids in adipose tissue.
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.
  
  
  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.
authors.affiliation: Department of Endocrinology and Diabetes, Leiden University Medical Center, Leiden, The Netherlands. A.M.den_Boer@lumc.nl
authors.forename: Marion A M
authors.initials: MA
authors.lastname: den Boer
authors.forename: Jimmy F P
authors.initials: JF
authors.lastname: Berbée
authors.forename: Peter
authors.initials: P
authors.lastname: Reiss
authors.forename: Marc
authors.initials: M
authors.lastname: van der Valk
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Voshol
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
authors.forename: Louis M
authors.initials: LM
authors.lastname: Havekes
authors.forename: Patrick C N
authors.initials: PC
authors.lastname: Rensen
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Romijn
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D053318:Apolipoprotein E3; D001057:Apolipoproteins E / Q000235:genetics; D015243:Cholesterol, VLDL / Q000096:biosynthesis / Q000097:blood; D004655:Emulsions; D004789:Enzyme Activation / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006493:Heparin / Q000494:pharmacology; D015228:Hypertriglyceridemia / Q000139:chemically induced* / Q000378:metabolism; D008066:Lipolysis / Q000187:drug effects*; D008071:Lipoprotein Lipase / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D019518:Postprandial Period; D019438:Ritonavir / Q000494:pharmacology*; D014280:Triglycerides / Q000096:biosynthesis / Q000097:blood; D014304:Triolein / Q000493:pharmacokinetics; D014316:Tritium
chemical_list: D000925:Anticoagulants; D053318:Apolipoprotein E3; D001057:Apolipoproteins E; D015243:Cholesterol, VLDL; D004655:Emulsions; D005227:Fatty Acids; D017320:HIV Protease Inhibitors; D014280:Triglycerides; C052720:apolipoprotein E3 (Leidein); D014316:Tritium; D014304:Triolein; D006493:Heparin; D008071:Lipoprotein Lipase; D019438:Ritonavir