Ritonavir impairs lipoprotein lipase-mediated lipolysis and decreases uptake of fatty acids in adipose tissue.
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.
den Boer
Marion A M
MA
Department of Endocrinology and Diabetes, Leiden University Medical Center, Leiden, The Netherlands. A.M.den_Boer@lumc.nl
Berbée
Jimmy F P
JF
Reiss
Peter
P
van der Valk
Marc
M
Voshol
Peter J
PJ
Kuipers
Folkert
F
Havekes
Louis M
LM
Rensen
Patrick C N
PC
Romijn
Johannes A
JA
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
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