title: The HIV protease inhibitor nelfinavir induces insulin resistance and increases basal lipolysis in 3T3-L1 adipocytes.
abstract: HIV protease inhibitors (HPIs) are potent antiretroviral agents clinically used in the management of HIV infection. Recently, HPI therapy has been linked to the development of a metabolic syndrome in which adipocyte insulin resistance appears to play a major role. In this study, we assessed the effect of nelfinavir on glucose uptake and lipolysis in differentiated 3T3-L1 adipocytes. An 18-h exposure to nelfinavir resulted in an impaired insulin-stimulated glucose uptake and activation of basal lipolysis. Impaired insulin stimulation of glucose up take occurred at nelfinavir concentrations >10 micromol/l (EC(50) = 20 micromol/l) and could be attributed to impaired GLUT4 translocation. Basal glycerol and free fatty acid (FFA) release were significantly enhanced with as low as 5 micromol/l nelfinavir, displaying fivefold stimulation of FFA release at 10 micromol/l. Yet, the antilipolytic action of insulin was preserved at this concentration. Potential underlying mechanisms for these metabolic effects included both impaired insulin stimulation of protein kinase B Ser 473 phosphorylation with preserved insulin receptor substrate tyrosine phosphorylation and decreased expression of the lipolysis regulator perilipin. Troglitazone pre- and cotreatment with nelfinavir partly protected the cells from the increase in basal lipolysis, but it had no effect on the impairment in insulin-stimulated glucose uptake induced by this HPI. This study demonstrates that nelfinavir induces insulin resistance and activates basal lipolysis in differentiated 3T3-L1 adipocytes, providing potential cellular mechanisms that may contribute to altered adipocyte metabolism in treated HIV patients.
authors.affiliation: S. Daniel Abraham Center for Health and Nutrition, Laboratory for Multi-Disciplinary Diabetes Research, Ben-Gurion University of the Negev, Beer-Sheva, IL-84105, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Rudich
authors.forename: S
authors.initials: S
authors.lastname: Vanounou
authors.forename: K
authors.initials: K
authors.lastname: Riesenberg
authors.forename: M
authors.initials: M
authors.lastname: Porat
authors.forename: A
authors.initials: A
authors.lastname: Tirosh
authors.forename: I
authors.initials: I
authors.lastname: Harman-Boehm
authors.forename: A S
authors.initials: AS
authors.lastname: Greenberg
authors.forename: F
authors.initials: F
authors.lastname: Schlaeffer
authors.forename: N
authors.initials: N
authors.lastname: Bashan
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000502:physiology*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D007333:Insulin Resistance; D008066:Lipolysis / Q000187:drug effects*; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D019888:Nelfinavir / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt
chemical_list: D051275:Glucose Transporter Type 4; D017320:HIV Protease Inhibitors; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D011518:Proto-Oncogene Proteins; C495693:Slc2a4 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019888:Nelfinavir; D005947:Glucose