title: HIV protease inhibitors induce metabolic dysfunction in part via increased JNK1/2 pro-inflammatory signaling in L6 cells.
abstract: Protease inhibitors (PIs), such as atazanavir sulfate and ritonavir, are used clinically to prevent the progression of HIV and are known to induce insulin resistance. To determine whether PI-mediated insulin resistance is induced by activation of pro-inflammatory cascades, L6 skeletal muscle cells were treated ±atazanavir sulfate, ritonavir, or atazanavir sulfate + ritonavir, and ±insulin. Treatment with atazanavir sulfate, ritonavir, or atazanavir sulfate + ritonavir for 24 or 48 h significantly increased basal glucose uptake (P<0.05) and atazanavir sulfate + ritonavir treatment increased basal glucose uptake significantly more than ritonavir or atazanavir sulfate treatment alone (P<0.05). Atazanavir sulfate + ritonavir treatment for 48 h completely prevented insulin stimulation of glucose uptake (P>0.05). When compared to untreated cells, basal palmitate uptake and oxidation was found to be significantly higher in cells treated with PIs alone or in combination (P<0.05). Prior PI treatment alone or in combination prevented (P>0.05) the insulin-mediated increase in palmitate uptake and the insulin-mediated decrease in palmitate oxidation observed in the control group. Atazanavir sulfate treatment alone or in combination with ritonavir significantly increased JNK1/2 phosphorylation when compared to the control or ritonavir group (P<0.05) and this was accompanied by a rise (P<0.05) in AKT(Ser473) phosphorylation in the basal state. Total JNK1/2 and p38 MAPK protein content and p38 MAPK phosphorylation state were not altered in any of the treatment groups (P>0.05). Our data indicate that, in muscle cells, PIs induce metabolic dysfunction that is not limited to insulin-sensitive metabolism and that is potentially mediated by a rise in JNK1/2 pro-inflammatory signaling.
authors.affiliation: Department of Biological Sciences, Dana and David Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, 90089-0652, USA.
authors.forename: Lindsey D
authors.initials: LD
authors.lastname: Bogachus
authors.forename: Lorraine P
authors.initials: LP
authors.lastname: Turcotte
mesh_terms: D000818:Animals; D000069446:Atazanavir Sulfate; D002460:Cell Line; D005947:Glucose / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D007333:Insulin Resistance; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D010168:Palmitates / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D019438:Ritonavir / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D010168:Palmitates; D011725:Pyridines; D000069446:Atazanavir Sulfate; D048056:Mitogen-Activated Protein Kinase 9; D051057:Proto-Oncogene Proteins c-akt; D048055:Mitogen-Activated Protein Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose; D019438:Ritonavir