Low lipolytic enzyme activity in patients with severe hypertriglyceridemia on highly active antiretroviral therapy

Hypertriglyceridemia was reported early in the use of highly active antiretroviral therapy (HAART) [1]. We assayed lipoprotein and hepatic triglyceride lipases, together with the apolipoprotein C and E phenotypes, in 12 HIV 1-infected men with severe hypertriglyceridemia (400−−4500 mg/dl). After a 12 h overnight fast, patients received an intravenous bolus of heparin (100 IU/kg). Pre-heparin and 10 min post-heparin plasma samples were immediately centrifuged and stored at −80°C. Lipoprotein and hepatic lipase activities were measured separately, twice in triplicate, using the Nilsson–Ehle method [2]. Activity was expressed in micromoles of free fatty acids (FFA) released from the radiolabelled emulsion per millilitre of plasma and per hour (μmol/ml/h). Within-run and between-run coefficients of variation were 6.8 and 7.9% for hepatic lipase, and 7.5 and 8.4% for lipoprotein, respectively. The apolipoprotein C-II to C-III1 plus C-III2ratio (hereafter referred to as the apo C-II : C-III ratio) [3] and apolipoprotein E phenotypes were determined in fasting samples by means of isoelectric focusing, according to Bouthillier et al. [4]. The results are summarized in Table 1. The body mass index was normal in the 10 patients in whom it was measured. Two patients (nos. 5 and 9) had abdominal lipodystrophy and one (no. 3) had facial fat wasting. Mean lipoprotein and hepatic lipase activities were 9.1 (± 4.0) and 8.6 (± 3.1) μmol FFA/ml per hour, respectively. The apo C-II : C-III ratio was normal in all but one of the patients (no. 1). Apolipoprotein E phenotypes were E3/E3 in eight patients, E2/E3 in two and E3/E4 in two.Table 1: History of HIV 1 infection in 12 patients on highly active antiretroviral therapy. All 12 patients had a marked decrease in hepatic lipase activity, and seven also had low lipoprotein activity. It was noticed that fasting levels of FFA were normal (not shown). Neither a lack of apolipoprotein C-II (lipoprotein-activating factor) nor an excess of apolipoprotein C-III (lipoprotein-inhibiting factor) explained the impaired lipoprotein activity. At this time, no activating or inhibiting factor for hepatic lipase modulation has been shown. Purnell et al. [6] recently reported a rapid decrease in hepatic lipase activity in HIV 1-seronegative volunteers receiving 15 day HAART, whereas lipoprotein activity remained normal. Tsiodras et al. [7] reported that severe hypertriglyceridemia appeared to be mainly linked to protease inhibitors (PI). In our patients (data not shown), hypertriglyceridemia appeared to be rather relevant to the accumulation of all triglyceride-rich lipoprotein (TRL) species but not to the sole VLDL hypersecretion, as suggested by Purnell et al. The increased levels of chylomicrons and VLDL were probably caused by the decrease in lipoprotein activity, whereas the accumulation of cholesterol- and apolipoprotein-E-rich remnants (chylomicron-remnant and intermediate density lipoprotein) would rather be caused by decreased hepatic lipase activity. The clearance of the TRL remnant is also dependent on the hepatic apolipoprotein-E receptor pathway. Because the distribution of the apolipoprotein-E phenotype was normal in our patients, the defective TRL metabolism may be caused by a direct interaction of PI with the LDL receptor-related protein, as suggested by Carr et al.[8]. Further metabolic investigations are required to explain the mechanisms of lipid disorders in this setting. To survey the occurrence of severe hypertriglyceridemia, we consider that fasting triglyceride and total cholesterol values should be frequently measured in HIV 1-infected patients on HAART. Acknowledgements The authors would like to thank Guenola Coste and Marie-Christine Federspiel for technical assistance, Ali Id Hammou for help with patient management, Joseph B. McCormick for his comments on the manuscript, and David Young for checking the English. Laurence Barila Isabel Beuclerb Marc-Antoine Valantina Eric Bruckertc Dominique Bonnefont-Rousselotd Anne Coutelliere Eric Caumesa Christine Katlamaa François Bricairea