Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance

Lancet. 1998 Jun 20;351(9119):1881-3. doi: 10.1016/S0140-6736(98)03391-1.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Cytochrome P-450 Enzyme System / drug effects
  • Diabetes Mellitus, Type 2 / chemically induced
  • Female
  • HIV Protease Inhibitors / adverse effects*
  • HIV Protease Inhibitors / chemistry
  • Humans
  • Hyperlipidemias / chemically induced*
  • Insulin Resistance* / physiology
  • Lipodystrophy / chemically induced*
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Obesity / chemically induced*
  • Receptors, Immunologic / drug effects
  • Receptors, Retinoic Acid / drug effects
  • Sequence Homology, Amino Acid


  • HIV Protease Inhibitors
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Receptors, Immunologic
  • Receptors, Retinoic Acid
  • retinoic acid binding protein I, cellular
  • Cytochrome P-450 Enzyme System