Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance.
HIV-1 protease-inhibitor treatments are associated with a syndrome of peripheral lipodystrophy, central adiposity, breast hypertrophy in women, hyperlipidaemia, and insulin resistance. The catalytic region of HIV-1 protease, to which protease inhibitors bind, has approximately 60% homology to regions within two proteins that regulate lipid metabolism: cytoplasmic retinoic-acid binding protein type 1 (CRABP-1) and low density lipoprotein-receptor-related protein (LRP). We hypothesise that protease inhibitors inhibit CRABP-1-modified, and cytochrome P450 3A-mediated synthesis of cis-9-retinoic acid, a key activator of the retinoid X receptor; and peroxisome proliferator activated receptor type gamma (PPAR-gamma) heterodimer, an adipocyte receptor that regulates peripheral adipocyte differentiation and apoptosis. Protease-inhibitor binding to LRP would impair hepatic chylomicron uptake and triglyceride clearance by the endothelial LRP-lipoprotein lipase complex. The resulting hyperlipidaemia contributes to central fat deposition (and in the breasts in the presence of oestrogen), insulin resistance, and, in susceptible individuals, type 2 diabetes. Understanding the syndrome's pathogenesis should lead to treatment strategies and to the design of protease inhibitors that do not cause this syndrome.
Carr
A
A
HIV Medicine Unit, St Vincent's Hospital, Sydney, Australia. acarr@stvincents.com.au
Samaras
K
K
Chisholm
D J
DJ
Cooper
D A
DA
D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced; D005260:Female; D017320:HIV Protease Inhibitors / Q000009:adverse effects* / Q000737:chemistry; D006801:Humans; D006949:Hyperlipidemias / Q000139:chemically induced*; D007333:Insulin Resistance / Q000502:physiology; D008060:Lipodystrophy / Q000139:chemically induced*; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D009765:Obesity / Q000139:chemically induced*; D011971:Receptors, Immunologic / Q000187:drug effects; D018168:Receptors, Retinoic Acid / Q000187:drug effects; D017386:Sequence Homology, Amino Acid
D017320:HIV Protease Inhibitors; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011971:Receptors, Immunologic; D018168:Receptors, Retinoic Acid; C082927:retinoic acid binding protein I, cellular; D003577:Cytochrome P-450 Enzyme System