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HIV protease inhibitors block human preadipocyte differentiation, but not via the PPARgamma/RXR heterodimer

J M Wentworth1, T P Burris, V K Chatterjee

  • 1Level 5, Department of Medicine, Addenbrookes, Cambridge CB2 2QQ, UK.

The Journal of Endocrinology
|February 5, 2000
PubMed

Insights

HIV protease inhibitors (PIs) cause lipodystrophy by impairing fat cell differentiation. This occurs independently of the PPARgamma/RXR nuclear receptor pathway, suggesting a novel mechanism for this metabolic side effect.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Endocrinology

Background:

  • Antiviral therapy with HIV protease inhibitors (PIs) is linked to lipodystrophy and metabolic dysfunction.
  • The exact mechanism underlying PI-associated lipodystrophy remains unclear.

Purpose of the Study:

  • To investigate the effects of specific HIV PIs (indinavir and saquinavir) on human preadipocyte differentiation.
  • To determine if PIs interfere with the PPARgamma/RXR nuclear receptor pathway involved in adipogenesis.

Main Methods:

  • Primary human preadipocytes were cultured.
  • The effects of indinavir and saquinavir on preadipocyte differentiation were assessed.
  • Transcriptional activation and adipocyte P2 gene induction mediated by PPARgamma/RXR were analyzed.

Main Results:

  • Indinavir and saquinavir were found to inhibit the differentiation of human preadipocytes.
  • These PIs did not inhibit transcriptional activation by the PPARgamma/RXR nuclear receptor heterodimer.
  • Adipocyte P2 gene induction by PPARgamma/RXR was also unaffected by the PIs.

Conclusions:

  • Impaired adipogenesis (fat cell formation) is likely the cause of lipodystrophy associated with HIV protease inhibitors.
  • This inhibition of adipogenesis occurs through a mechanism independent of the PPARgamma/RXR nuclear receptor pathway.

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