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

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• 作者：Lindsey D.  ; Bogachus^a ;   ; ^b ; Lorraine P.  ; Turcotte^a ;   ; ^b ;   ; ^{turcotte@usc.edu}
• 关键词：Glucose uptake ; p38 MAPK (Mitogen Activated Protein Kinase) ; Inflammation ; AKT2 ; Fatty acid oxidation
• 刊名：Antiviral Research
• 出版年：2011
• 出版时间：December 2011
• 年：2011
• 卷：92
• 期：3
• 页码：415-423
• 全文大小：679 K

文摘

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 ¡Àatazanavir sulfate, ritonavir, or atazanavir sulfate + ritonavir, and ¡Àinsulin. 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.