title: Effects of ritonavir-boosted darunavir, atazanavir and lopinavir on adipose functions and insulin sensitivity in murine and human adipocytes.
abstract: BACKGROUND
  Ritonavir-boosted protease inhibitors (PIs) could adversely affect metabolism and adipose tissue to different extents, depending on the molecule. Using drugs with minimal adverse metabolic effects is an important consideration in at-risk HIV-infected patients. In vitro adipocyte models can be useful for comparing the effects of different PIs.
  
  
  METHODS
  We compared the effects of darunavir, darunavir/ritonavir, atazanavir/ritonavir and lopinavir/ritonavir in murine and human adipocytes on differentiation, mitochondrial function, reactive oxygen species (ROS) production and insulin sensitivity.
  
  
  RESULTS
  In human and murine adipocytes, differentiation evaluated by lipid content and protein expression of adipogenic markers, mitochondrial function evaluated by aggregation of the cationic dye JC-1 and by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide lysis, and mitochondrial mass evaluated by MitoTracker fluorescence and the expression of mitochondrial proteins were unaffected by darunavir, mildly affected by darunavir/ritonavir and further altered by atazanavir/ritonavir and lopinavir/ritonavir. ROS production was unaltered by darunavir and darunavir/ritonavir but was increased by lopinavir/ritonavir and atazanavir/ritonavir. Regarding insulin sensitivity, darunavir and darunavir/ritonavir had no significant effect on insulin activation of protein kinase B (Akt/PKB) and MAP kinase and of glucose transport, whereas lopinavir/ritonavir and atazanavir/ritonavir partly impaired the effect of insulin. The effect of atazanavir/ritonavir was generally milder than that of lopinavir/ritonavir.
  
  
  CONCLUSIONS
  The various PIs differentially modified adipocyte functions. Darunavir alone did not affect adipocyte functions and only modestly altered differentiation and mitochondrial function when associated with ritonavir. Lopinavir/ritonavir adversely affected differentiation and lipid content, mitochondrial function, ROS production and insulin sensitivity, and the effect of atazanavir/ritonavir was intermediate. Thus, in vitro, darunavir/ritonavir presented a safer metabolic profile on adipocytes than atazanavir/ritonavir and lopinavir/ritonavir.
authors.affiliation: INSERM, UMR_S 938, Faculté de Médecine Saint Antoine, Paris, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Capel
authors.forename: Martine
authors.initials: M
authors.lastname: Auclair
authors.forename: Martine
authors.initials: M
authors.lastname: Caron-Debarle
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Capeau
mesh_terms: D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D000069446:Atazanavir Sulfate; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D000069454:Darunavir; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D007333:Insulin Resistance; D008066:Lipolysis / Q000187:drug effects; D061466:Lopinavir / Q000009:adverse effects / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000009:adverse effects / Q000494:pharmacology; D011725:Pyridines / Q000009:adverse effects / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D019438:Ritonavir / Q000009:adverse effects / Q000494:pharmacology*; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D061466:Lopinavir; D000069446:Atazanavir Sulfate; D019438:Ritonavir; D000069454:Darunavir