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

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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;P3H]oleate-labeled VLDL–like emulsion particles (half time, 19.3±10.5 versus 5.0±1.3 minutes in controls;PConclusions—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.

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