Stearic acid induces proinflammatory cytokine production partly through activation of lactate-HIF1α pathway in chondrocytes.
The biomechanics stress and chronic inflammation in obesity are causally linked to osteoarthritis. However, the metabolic factors mediating obesity-related osteoarthritis are still obscure. Here we scanned and identified at least two elevated metabolites (stearic acid and lactate) from the plasma of diet-induced obese mice. We found that stearic acid potentiated LDH-a-dependent production of lactate, which further stabilized HIF1α protein and increased VEGF and proinflammatory cytokine expression in primary mouse chondrocytes. Treatment with LDH-a and HIF1α inhibitors notably attenuated stearic acid-or high fat diet-stimulated proinflammatory cytokine production in vitro and in vivo. Furthermore, positive correlation of plasma lactate, cartilage HIF1α and cytokine levels with the body mass index was observed in subjects with osteoarthritis. In conclusion, saturated free fatty acid induced proinflammatory cytokine production partly through activation of a novel lactate-HIF1α pathway in chondrocytes. Our findings hold promise of developing novel clinical strategies for the management of obesity-related diseases such as osteoarthritis.
Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Hongming
H
Miao
Department of Orthopedics, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
Liang
L
Chen
Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Lijun
L
Hao
Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Xuan
X
Zhang
Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Yujuan
Y
Chen
Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Zhihua
Z
Ruan
Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Houjie
H
Liang
D000818:Animals; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D059305:Diet, High-Fat / Q000379:methods; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000276:immunology*; D018836:Inflammation Mediators / Q000276:immunology*; D019344:Lactic Acid / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000276:immunology; D013229:Stearic Acids / Q000276:immunology*; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology
D016207:Cytokines; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018836:Inflammation Mediators; D013229:Stearic Acids; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D019344:Lactic Acid; C031183:stearic acid