on November 3, 2005
Published online before print November 3, 2005, doi: 10.1161/01.ATV.0000194073.87647.10
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Submitted on August 23, 2005
Accepted on October 20, 2005
Ritonavir Impairs Lipoprotein Lipase-Mediated Lipolysis and Decreases Uptake of Fatty Acids in Adipose Tissue
Marion A.M. den Boer *;
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.), LUMC, Leiden; TNO-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.), AMC, Amsterdam; and Laboratory of Pediatrics (F.K.), Center for Liver, Digestive, and Metabolic Diseases, University Hospital Groningen, Groningen, the Netherlands.
* To whom correspondence should be addressed. 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.
Key words: dyslipidemia • protease inhibitor • transgenic mice • FA metabolism • TG metabolism
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- HIV Protease Inhibitors and Hyperlipidemia: A Fatty Acid Connection
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