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Abstract
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.