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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

FFA and lactate enhance production of proinflammatory cytokines and VEGF via HIF1α in mouse chondrocytes.(a) Immunoblotting assay of HIF1α in primary chondrocytes transfected with a scramble siRNA (siNC, 20 nM), a mouse HIF1α specific siRNA1 (siH-1, 20 nM) or siRNA2 (siH-2, 20 nM) for 36 h. (b~e) Relative mRNA levels of IL-6 (b), TNF-α (c), IL-1β (d) and VEGF (e) in the mouse primary chondrocytes transfected with siNC (20 nM), siH-1 (20 nM) or siH-2 (20 nM)for 12 h plus additional treatment with BSA (5%) or FFA (200 μM) for 24 h. Values not sharing a common superscript letter differ significantly. (n = 3, P < 0.05). (f~i) Relative mRNA levels of IL-6 (f), TNF-α (g), IL-1β (h) and VEGF (i) in the mouse primary chondrocytes transfected with siNC (20 nM), siH-1 (20 nM) or siH-2 (20 nM) for 12 h plus additional treatment with lactate (25 mM) or vehicle control for 24 h. Values not sharing a common superscript letter differ significantly. (n = 3, P < 0.05).
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f4: FFA and lactate enhance production of proinflammatory cytokines and VEGF via HIF1α in mouse chondrocytes.(a) Immunoblotting assay of HIF1α in primary chondrocytes transfected with a scramble siRNA (siNC, 20 nM), a mouse HIF1α specific siRNA1 (siH-1, 20 nM) or siRNA2 (siH-2, 20 nM) for 36 h. (b~e) Relative mRNA levels of IL-6 (b), TNF-α (c), IL-1β (d) and VEGF (e) in the mouse primary chondrocytes transfected with siNC (20 nM), siH-1 (20 nM) or siH-2 (20 nM)for 12 h plus additional treatment with BSA (5%) or FFA (200 μM) for 24 h. Values not sharing a common superscript letter differ significantly. (n = 3, P < 0.05). (f~i) Relative mRNA levels of IL-6 (f), TNF-α (g), IL-1β (h) and VEGF (i) in the mouse primary chondrocytes transfected with siNC (20 nM), siH-1 (20 nM) or siH-2 (20 nM) for 12 h plus additional treatment with lactate (25 mM) or vehicle control for 24 h. Values not sharing a common superscript letter differ significantly. (n = 3, P < 0.05).

Mentions: To verify whether stearic acid and lactate induced cytokine production through HIF1α, mouse HIF1α specific siRNAs were employed to silence the expression of HIF1α in primary mouse chondrocytes (Fig. 4a). As expected, stearic acid-induced production of IL-6 (Fig. 4b), TNF-α (Fig. 4c) and IL-1β (Fig. 4d) could be partly blocked by HIF1α silence, while stearic acid-stimulated VEGF expression was fully prevented by HIF1α deletion (Fig. 4e). In contrast, lactate-induced expression of IL-6 (Fig. 4f), TNF-α (Fig. 4g), IL-1β (Fig. 4h) and VEGF (Fig. 4i) could be fully diminished by HIF1α silence. Those results indicated that stearic acid mediated inflammation response partly through HIF1α, while lactate induced inflammation response in a HIF1α-dependent manner in chondrocytes.


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)

FFA and lactate enhance production of proinflammatory cytokines and VEGF via HIF1α in mouse chondrocytes.(a) Immunoblotting assay of HIF1α in primary chondrocytes transfected with a scramble siRNA (siNC, 20 nM), a mouse HIF1α specific siRNA1 (siH-1, 20 nM) or siRNA2 (siH-2, 20 nM) for 36 h. (b~e) Relative mRNA levels of IL-6 (b), TNF-α (c), IL-1β (d) and VEGF (e) in the mouse primary chondrocytes transfected with siNC (20 nM), siH-1 (20 nM) or siH-2 (20 nM)for 12 h plus additional treatment with BSA (5%) or FFA (200 μM) for 24 h. Values not sharing a common superscript letter differ significantly. (n = 3, P < 0.05). (f~i) Relative mRNA levels of IL-6 (f), TNF-α (g), IL-1β (h) and VEGF (i) in the mouse primary chondrocytes transfected with siNC (20 nM), siH-1 (20 nM) or siH-2 (20 nM) for 12 h plus additional treatment with lactate (25 mM) or vehicle control for 24 h. Values not sharing a common superscript letter differ significantly. (n = 3, P < 0.05).
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Related In: Results  -  Collection

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f4: FFA and lactate enhance production of proinflammatory cytokines and VEGF via HIF1α in mouse chondrocytes.(a) Immunoblotting assay of HIF1α in primary chondrocytes transfected with a scramble siRNA (siNC, 20 nM), a mouse HIF1α specific siRNA1 (siH-1, 20 nM) or siRNA2 (siH-2, 20 nM) for 36 h. (b~e) Relative mRNA levels of IL-6 (b), TNF-α (c), IL-1β (d) and VEGF (e) in the mouse primary chondrocytes transfected with siNC (20 nM), siH-1 (20 nM) or siH-2 (20 nM)for 12 h plus additional treatment with BSA (5%) or FFA (200 μM) for 24 h. Values not sharing a common superscript letter differ significantly. (n = 3, P < 0.05). (f~i) Relative mRNA levels of IL-6 (f), TNF-α (g), IL-1β (h) and VEGF (i) in the mouse primary chondrocytes transfected with siNC (20 nM), siH-1 (20 nM) or siH-2 (20 nM) for 12 h plus additional treatment with lactate (25 mM) or vehicle control for 24 h. Values not sharing a common superscript letter differ significantly. (n = 3, P < 0.05).
Mentions: To verify whether stearic acid and lactate induced cytokine production through HIF1α, mouse HIF1α specific siRNAs were employed to silence the expression of HIF1α in primary mouse chondrocytes (Fig. 4a). As expected, stearic acid-induced production of IL-6 (Fig. 4b), TNF-α (Fig. 4c) and IL-1β (Fig. 4d) could be partly blocked by HIF1α silence, while stearic acid-stimulated VEGF expression was fully prevented by HIF1α deletion (Fig. 4e). In contrast, lactate-induced expression of IL-6 (Fig. 4f), TNF-α (Fig. 4g), IL-1β (Fig. 4h) and VEGF (Fig. 4i) could be fully diminished by HIF1α silence. Those results indicated that stearic acid mediated inflammation response partly through HIF1α, while lactate induced inflammation response in a HIF1α-dependent manner in chondrocytes.

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