Lopinavir co-induces insulin resistance and ER stress in human adipocytes.
HIV-protease inhibitors (PIs) markedly decreased mortality of HIV-infected patients. However, their use has been associated with occurence of metabolic abnormalities the causes of which are not well understood. We report here that lopinavir, one of the most prescribed PI, dose-dependently co-induced insulin resistance and ER stress in human adipocytes obtained from differentiation of precursor cells. Insulin resistance was subsequent to IRS1 phosphorylation defects and resulted in a concentration-dependent decrease of glucose uptake. The major ER stress pathway involved was the phosphorylation of eIF2-alpha. Salubrinal, a selective eIF2-alpha dephosphorylation inhibitor, induced insulin resistance by targeting IRS1 phosphorylation at serine 312 and acted synergistically with LPV when both drugs were used in combination. This study points out the key role of eIF2-alpha phosphorylation in the development of PI-associated insulin resistance and ER stress. Thus, this protein represents a promising therapeutic target for development of new PIs devoid of adverse metabolic effects.
Djedaini
Mansour
M
Institute of Biology Development and Cancer, University of Nice Sophia-Antipolis, CNRS, 28 Avenue de Valombrose, 06107 NICE Cedex2, France.
Peraldi
Pascal
P
Drici
Milou-Daniel
MD
Darini
Cédric
C
Saint-Marc
Perla
P
Dani
Christian
C
Ladoux
Annie
A
D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D002934:Cinnamates / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D061466:Lopinavir; D010766:Phosphorylation; D011744:Pyrimidinones / Q000009:adverse effects* / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
D002934:Cinnamates; D015852:Eukaryotic Initiation Factor-2; D017320:HIV Protease Inhibitors; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D011744:Pyrimidinones; C496827:salubrinal; D061466:Lopinavir; D013890:Thiourea