WESTPORT, CT (Reuters Health) Dec 20 - HIV protease inhibitors appear to induce hyperlipidemia by stimulating the hepatic synthesis of triglycerides, according to a report published in the December issue of Arteriosclerosis, Thrombosis, and Vascular Biology.
Dr. James M. Lenhard and colleagues, from GlaxoWellcome Inc., Research Triangle Park, North Carolina, studied the impact of various HIV protease inhibitors on lipid metabolism using an in vitro liver cell culture and a murine model.
Based on the in vitro analysis, the investigators found that ABT-378, nelfinavir, ritonavir, and saquinavir stimulated triglyceride synthesis. Cholesterol synthesis increased with ritonavir, but was unaffected by amprenavir and indinavir. Messenger RNA expression of diacylglycerol acyltransferase and fatty acid synthase was increased with nelfinavir.
In addition, the protease inhibitor-induced effects on triglyceride synthesis and fatty acid synthase mRNA expression were augmented by the retinoid X receptor agonist LG100268.
While triglycerides increased with nelfinavir or ritonavir in fed mice, only ritonavir produced an effect in fasted mice, the authors note. This finding suggests that "these protease inhibitors have different effects on metabolism." However, when the triglyceride clearance inhibitor Triton WR-1339 was given, both nelfinavir and ritonavir produced a 2- to 3-fold increase in triglycerides in fasted mice.
"Considering the importance of liver in lipoprotein metabolism, there have been surprisingly few reports that examined the effects of protease inhibitors on hepatocytes," the researchers mention. Combined with other observations, the current findings "indicate that select protease inhibitors affect multiple, distinct metabolic pathways, perhaps accounting for the different side effects observed for each protease inhibitor in the clinic."
Although the results with Triton WR-1339 suggest that protease inhibitors affect lipid synthesis and not clearance, further studies are needed to confirm this. Also, "the interaction between protease inhibitors and retinoid signaling pathways may be an important mechanism by which protease inhibitors affect lipid metabolism," the researchers point out.
"Consistent with the hypothesis that the effects of protease inhibitors on metabolism can be influenced by diet, protease inhibitors have different effects on lipid metabolism in mice fed a high- or low-fat diet," the authors note. "The variability of metabolic changes reported in the clinic situation may depend on food restrictions associated with select protease inhibitors," they postulate.
Arterioscler Thromb Vasc Biol 2000;20:2625-2629.
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