Stearic acid induces proinflammatory cytokine production partly through activation of lactate-HIF1α pathway in chondrocytes

Abstract

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.

Oxamate Enhances the Anti-Inflammatory and Insulin-Sensitizing Effects of Metformin in Diabetic Mice

“…Furthermore, its ability to improve inflammation and insulin sensitivity, especially over long-term use, may be attenuated by its induction of elevated tissue lactate and blood lactate levels [6,10,11], as lactate possesses proinflammatory properties and can lead to IR [16,17,18,25,28,29,30]. However, OXA can inhibit tissue lactate production and decrease blood lactate levels, thus not only improving inflammation and IR itself but also enhancing the effects of MET.…”

“…In addition, recent studies have shown that lactate may further act as a signal molecule in the pro-inflammatory signaling pathway. For example, lactate promotes the production of pro-inflammatory cytokines (e.g., TNF-α, IL-6) in macrophages, endothelial cells, meshwork cells, T cells, and chondrocytes, and also increases the DNA-binding activity of nuclear factor-kappa B (NF-κB) in L6 myogenic cells [16,17,18,28,29,30]. In contrast, OXA has an anti-inflammatory effect through the inhibition of lactate production [18,31].…”

“…For example, lactate promotes the production of pro-inflammatory cytokines (e.g., TNF-α, IL-6) in macrophages, endothelial cells, meshwork cells, T cells, and chondrocytes, and also increases the DNA-binding activity of nuclear factor-kappa B (NF-κB) in L6 myogenic cells [16,17,18,28,29,30]. In contrast, OXA has an anti-inflammatory effect through the inhibition of lactate production [18,31]. OXA inhibits the NF-κB activation and improves IR induced by free fatty acids in myotubes, and inhibits the production of pro-inflammatory cytokines induced by free fatty acids in chondrocytes [18,31].…”

“…In contrast, OXA has an anti-inflammatory effect through the inhibition of lactate production [18,31]. OXA inhibits the NF-κB activation and improves IR induced by free fatty acids in myotubes, and inhibits the production of pro-inflammatory cytokines induced by free fatty acids in chondrocytes [18,31]. In this study, we showed that increased tissue lactate production and blood lactate levels were accompanied with higher levels of inflammation, IR, and blood glucose in db/db mice, and that OXA has anti-inflammatory, anti-IR, and anti-diabetic properties.…”

“…Furthermore, recent studies have shown that lactate may also constitute a signal molecule in the pro-inflammatory signaling pathway [16,17,18], which plays an important role in the development of IR and T2DM [19]. Numerous studies, including cross-sectional and prospective studies, have found that blood lactate is elevated among patients with obesity, a condition associated with IR, and that blood lactate may represent an independent risk factor for the development of T2DM [20,21,22,23].…”