HypothesisPathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance
Section snippets
Molecular homologies
HIV-1 protease inhibitors have high affinity for the catalytic site of HIV-1 protease,6 and so might cause this syndrome by binding and inhibiting an homologous human protein involved in lipid metabolism. We compared a 12 aminoacid sequence (aa 19 to 30; figure 1) about the catalytic region of HIV-1 protease to all mammalian protein and genome sequences in GenBank, EMBASE, and Swiss protein libraries. This sequence has homologies at the protein level of 63% with a region incorporating a
Cytoplasmic retinoic-acid binding protein type 1
CRABP-1 is a ubiquitous protein that binds virtually all intracellular retinoic acid.7, 8 CRABP-1 presents retinoic acid to cytochrome P450 3A isoforms which catalyse the conversion of retinoic acid to cis-9-retinoic acid9 (figure 2). Cis-9-retinoic acid in turn is the sole ligand of the retinoid X receptor (RXR).9, 10 In adipocyte nuclei, RXR functions as a heterodimer with peroxisome-proliferator-activated receptor type gama (PPAR-γ). Ligand binding to RXR or PPAR-γ inhibits adipocyte
Cytochrome P450
Cytochrome P450 3A is the only enzyme known to convert retinoic acid to cis-9-retinoic acid. HIV-1 protease inhibitors are potent inhibitors of cytochrome P450 3A. We suggest that the altered fat metabolism would in part be proportional to the degree of cytochrome P450 inhibition. Indeed, lipodystrophy appears to be worst in those receiving ritonavir,1 the most potent cytochrome P450 3A-inhibitor of the protease inhibitors.
Low-density lipoprotein-receptor-related protein
LRP is an hepatic receptor important for post-prandial chylomicron clearance.17, 18 LRP is also co-expressed on capillary endothelium wth lipoprotein lipase (LPL). The LPL-LRP complex cleaves fatty acids from circulating triglycerides, permitting free fatty acid entry into adipocytes for storage at fat.19 The GQDDC sequence of the homologous region in LRP is indeed a lipid binding domain (figure 1). Protease-inhibitor binding of hepatic and endothelial LRP would, therefore, exacerbate
Hypothesis
HIV-1 protease inhibitor-induced peripheral lipodystrophy is a result of impaired CRABP1-mediated cis-9-retinoic acid stimulation of RXR:PPAR-γ, resulting in reduced differentiation and increased apoptosis of peripheral adipocytes, with impaired fat storage and lipid release. The syndrome's severity is in part proportional to a protease inhibitor's capacity to inhibit cytochrome P450 3A. Secondary hyperlipidaemia is exacerbated by inhibition of LRP, leading to central obesity, breast fat
Testing the hypothesis
In-vitro binding studies could examine the functional effects of HIV-1 protease inhibitors on LRP by assessing chylomicron uptake on hepatocytes and lipoprotein lipase activity. The effects on CRABP-1 could be assessed by measuring retinoic-acid binding to purified CRABP-1 and intracellular cis-9-retinoic acid production in cultured adipocytes.
Assuming that protease-inhibitor to CRABP-1 and LRP is not permanent, in-vivo studies should show that the syndrome is reversible, although peripheral
Future protease inhibitor development
CRABP-1 and LRP are not aspartyl proteases, which may explain why they were not considered potential targets of HIV-1-protease inhibitors in preclinical development. Nevertheless, protease inhibitors also inhibit numerous cytochrome P450 isoforms that are not aspartyl proteases and which have substantially less homology about the HIV-1 protease catalytic site than CRABP-1 or LRP. If our hypothesis is correct, future development plans for viral protease inhibitors should include evaluation of
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