7th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 13–16 November 2005, Dublin, Ireland

Ritonavir impairs lipoprotein lipase-mediated lipolysis and decreases uptake of fatty acids in adipose tissue

MAM den Boer^1,2, JFP Berbée^2,3, P Reiss⁴, M van der Valk⁴, PJ Voshol^1,2, F Kuipers⁵, LM Havekes^2,3,6, PCN Rensen^2,3 and JA Romijn^1
1Department of Endocrinology and Diabetes, LUMC, Leiden; ²TNO-Quality of Life, Leiden; ³Department of General Internal Medicine, LUMC, Leiden; ⁴Department of Infectious Diseases, Tropical Medicine and AIDS, AMC, Amsterdam; ⁵Laboratory of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University Hospital Groningen, Groningen; ⁶Department of Cardiology, LUMC, Leiden, Netherlands

Antiviral Therapy 2005; Supplement 3:L9 (abstract no. 11)

OBJECTIVES: The use of the HIV protease inhibitor ritonavir (RTV) is frequently associated with hypertriglyceridaemia and lipodystrophy. The first aim of the present study was to assess the effects of RTV on both VLDL-triglyceride (VLDL-TG) production and clearance rates. The second aim was to evaluate the effects of RTV on tissue-specific uptake of fatty acids (FAs) derived from VLDL-TG and from the plasma free FA pool.

METHODS AND RESULTS: We used the APOE*3-Leiden transgenic mouse as an experimental model, because these mice have a humanized lipoprotein profile and are susceptible to diet- and drug-induced hyperlipidaemia, obesity and atherosclerosis. Mice were fed a western-type diet supplemented with RTV (35mg/kg/day) for 2 weeks, resulting in a twofold increase in fasting plasma TG levels, which was specific for VLDL. RTV did not change the hepatic VLDL-TG production. Instead, RTV did increase the postprandial TG response to an oral fat load (AUC 25.5 ±12.1 vs 13.8 ±6.8 mM.h in controls; P<0.05). Likewise, RTV hampered the plasma clearance of intravenously injected glycerol tri[3H]oleate-labelled VLDL-like emulsion particles (t_½ 19.3±10.5 vs 5.0±1.3 min in controls; P<0.05), associated with a decrease of 44% in plasma LPL activity. We applied our recently described method using differentially labelled FAs to quantify tissue-specific uptake of FAs derived from VLDL-TG and from plasma free FA. RTV decreased the uptake of TG-derived FAs, as well as the uptake of albumin-bound FA, both specifically into adipose tissue.

CONCLUSIONS: We conclude that RTV causes hypertriglyceridaemia via decreased LPL-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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2005-11-13
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