HIV protease inhibitors induce metabolic dysfunction in part via increased JNK1/2 pro-inflammatory signaling in L6 cells

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 AKTSer473 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.

► Atazanavir sulfate + ritonavir treatment increases glucose and fatty acid metabolism. ► Atazanavir sulfate + ritonavir treatment induces a pro-inflammatory state. ► The protease inhibitor-induced pro-inflammatory state induces insulin resistance.