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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:124.)
© 2006 American Heart Association, Inc.

Vascular Biology

Ritonavir Impairs Lipoprotein Lipase–Mediated Lipolysis and Decreases Uptake of Fatty Acids in Adipose Tissue

Marion A.M. den Boer; Jimmy F.P. Berbée; Peter Reiss; Marc van der Valk; Peter J. Voshol; Folkert Kuipers; Louis M. Havekes; Patrick C.N. Rensen; Johannes A. Romijn

From the Departments of Endocrinology and Diabetes (M.A.M.d.B., P.J.V., J.A.R.), General Internal Medicine (J.F.P.B., L.M.H., P.C.N.R.), and Cardiology (L.M.H.), Leiden University Medical Center, Leiden; Netherlands Organization for Applied Scientific Research-Quality of Life (M.A.M.d.B., J.F.P.B., P.J.V., L.M.H., P.C.N.R.), Leiden; Department of Infectious Diseases, Tropical Medicine, and AIDS (P.R., M.v.d.V.), Amsterdam Medical Center, Amsterdam; and Laboratory of Pediatrics (F.K.), Center for Liver, Digestive, and Metabolic Diseases, University Hospital Groningen, Groningen, the Netherlands.

Correspondence to Marion A.M. den Boer, Department of Endocrinology and Diabetes, LUMC, PO Box 9600, 2300 RC Leiden, the Netherlands. E-mail A.M.den_Boer{at}lumc.nl

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.

We investigated the mechanism underlying the hypertriglyceridemia associated with ritonavir treatment in APOE*3-Leiden mice. Ritonavir increased the postprandial triglyceride response and decreased the clearance of glycerol tri[3H]oleatelabeled very low density lipoprotein-like emulsion particles, as related to decreased plasma lipoprotein lipase activity. These effects were accompanied by decreased fatty acid flux into adipose tissue.

Key Words: dyslipidemia • protease inhibitor • transgenic mice • FA metabolism • TG metabolism

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HIV Protease Inhibitors and Hyperlipidemia: A Fatty Acid Connection

Arthur A. Spector
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