1st International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 26–28 June 1999 - San Diego, CA, USA

LIPID METABOLISM AND LIPODYSTROPHIES

Antiviral Therapy 1999; 4(Suppl. 2):7 (abstract no. 2)

Stephen L Sturley and Richard J Deckelbaum
Institute of Human Nutrition, Columbia University, New York, NY

Several drug-specific toxicities with indinavir (renal caniculi), ritonavir (nausea, diarrhoea and peri-oral paraesthesiae) or nelfinavir (diarrhoea) have been observed. However, multiple studies are now documenting lipid-related syndromes as a frequent side effect of protease inhibition. Commonly this has been noted as a marked fat wasting and redistribution (particularly to the abdomen, thus termed "protease paunch", insulin resistant diabetes mellitus and hyperlipidemia. Studies of several patient groups observed 2- to threefold elevations in serum triglycerides with moderate (~30%) increases in cholesterol levels after as little as 2 months treatment.

The observation of hypertriglyceridemia induced by protease inhibitor therapy, suggests a defect in the handling of triglyceride rich lipoprotein particles such as very low density lipoproteins (VLDL) and chylomicrons. The Low Density Lipoprotein Receptor Related Protein (LRP) and RAP proteins are critical components of this aspect of lipid metabolism. Carr and colleagues identified significant but limited sequence similarity (7/12 identity over a 12 amino acid region) between the active site of the HIV protease (residues 19–30) and the LRP (residues 2919–2930). The homology between these proteins is duplicated at three more points within the molecule. The HIV-PR-homology resides in two complement-type domains of the LRP molecule responsible for ligand binding (region II, residues 836–2501 and region III, residues 2502–3315). Interestingly, no sequence identity between the closely related LDL or VLDL receptors was observed. The LRP was originally identified as a binding component of apolipoprotein (apo) E enriched particles, independent of the classical LDL receptor. Unlike the LDL-receptor, the ligands for the LRP are numerous; in addition to LDL-receptor ligands (apo E and apo B), they include lipoprotein lipase, hepatic lipase, a2-macroglobulin, tissue-type plasminogen activator, plasminogen activator inhibitor-1 and RAP. The critical role of the LRP in triglyceride metabolism was confirmed by tissue specific deletion or attenuation of the LRP. Under these circumstances, reduced LRP activity results in decreased lipoprotein-remnant clearance and two to threefold elevations in plasma triglyceride and cholesterol. This is very similar to the changes observed with HIV-PR therapy. This overview will summarise the basic concepts underlying lipodystrophies, with special emphasis on hypertriglyceridemias.

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