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

Miao H, Chen L, Hao L, Zhang X, Chen Y, Ruan Z, Liang H - Sci Rep (2015)

Bottom Line: 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.In conclusion, saturated free fatty acid induced proinflammatory cytokine production partly through activation of a novel lactate-HIF1α pathway in chondrocytes.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.

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.

No MeSH data available.


Related in: MedlinePlus

Proposed models for FFA/lactate-mediated HIF1α-cytokine axis in obesity-related osteoarthritis.Briefly, circulatory levels of saturate FFA are increased in diet-induced obesity. Saturated FFA could stimulate proinflammatory cytokine production in chondrocytes directly through TLR4. Meanwhile, the elevated FFA stimulates LDH-a-dependent lactate production in chondrocytes and perhaps also in other cells. Consequently, the levels of circulatory lactate are also increased in response to HFD treatment. The increased lactate would stabilize and activate HIF-1α protein in chondrocytes to stimulate the production of VEGF and proinflammatory cytokines. In summary, saturated FFA could stimulate proinflammatory cytokine production in chondrocytes directly through TLR4 or LDHa-lactate-HIF1α pathway, which provides a potential molecular mechanism linking obesity to chronic inflammation in osteoarthritis.
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f8: Proposed models for FFA/lactate-mediated HIF1α-cytokine axis in obesity-related osteoarthritis.Briefly, circulatory levels of saturate FFA are increased in diet-induced obesity. Saturated FFA could stimulate proinflammatory cytokine production in chondrocytes directly through TLR4. Meanwhile, the elevated FFA stimulates LDH-a-dependent lactate production in chondrocytes and perhaps also in other cells. Consequently, the levels of circulatory lactate are also increased in response to HFD treatment. The increased lactate would stabilize and activate HIF-1α protein in chondrocytes to stimulate the production of VEGF and proinflammatory cytokines. In summary, saturated FFA could stimulate proinflammatory cytokine production in chondrocytes directly through TLR4 or LDHa-lactate-HIF1α pathway, which provides a potential molecular mechanism linking obesity to chronic inflammation in osteoarthritis.

Mentions: In all, we identified that elevated circulatory metabolite stearic acid increased lactate levels in the plasma and chondrocytes in a LDH-a-dependent manner. The stearic acid stimulated VEGF and proinflammatory cytokine production through a canonic TLR4 pathway and a novel lactate/HIF1α pathway (Fig. 8). The molecules in both pathways might be potential diagnostic markers and functional therapeutic targets.


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

Miao H, Chen L, Hao L, Zhang X, Chen Y, Ruan Z, Liang H - Sci Rep (2015)

Proposed models for FFA/lactate-mediated HIF1α-cytokine axis in obesity-related osteoarthritis.Briefly, circulatory levels of saturate FFA are increased in diet-induced obesity. Saturated FFA could stimulate proinflammatory cytokine production in chondrocytes directly through TLR4. Meanwhile, the elevated FFA stimulates LDH-a-dependent lactate production in chondrocytes and perhaps also in other cells. Consequently, the levels of circulatory lactate are also increased in response to HFD treatment. The increased lactate would stabilize and activate HIF-1α protein in chondrocytes to stimulate the production of VEGF and proinflammatory cytokines. In summary, saturated FFA could stimulate proinflammatory cytokine production in chondrocytes directly through TLR4 or LDHa-lactate-HIF1α pathway, which provides a potential molecular mechanism linking obesity to chronic inflammation in osteoarthritis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4536527&req=5

f8: Proposed models for FFA/lactate-mediated HIF1α-cytokine axis in obesity-related osteoarthritis.Briefly, circulatory levels of saturate FFA are increased in diet-induced obesity. Saturated FFA could stimulate proinflammatory cytokine production in chondrocytes directly through TLR4. Meanwhile, the elevated FFA stimulates LDH-a-dependent lactate production in chondrocytes and perhaps also in other cells. Consequently, the levels of circulatory lactate are also increased in response to HFD treatment. The increased lactate would stabilize and activate HIF-1α protein in chondrocytes to stimulate the production of VEGF and proinflammatory cytokines. In summary, saturated FFA could stimulate proinflammatory cytokine production in chondrocytes directly through TLR4 or LDHa-lactate-HIF1α pathway, which provides a potential molecular mechanism linking obesity to chronic inflammation in osteoarthritis.
Mentions: In all, we identified that elevated circulatory metabolite stearic acid increased lactate levels in the plasma and chondrocytes in a LDH-a-dependent manner. The stearic acid stimulated VEGF and proinflammatory cytokine production through a canonic TLR4 pathway and a novel lactate/HIF1α pathway (Fig. 8). The molecules in both pathways might be potential diagnostic markers and functional therapeutic targets.

Bottom Line: 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.In conclusion, saturated free fatty acid induced proinflammatory cytokine production partly through activation of a novel lactate-HIF1α pathway in chondrocytes.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.

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.

No MeSH data available.


Related in: MedlinePlus