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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 potentiate HIF1α protein activity in mouse chondrocytes.(a) Immunoblotting assay of HIF1α in mouse primary chondrocytes treated with normal oxygen (Normoxia, 20% O2), low oxygen (hypoxia, 0.1% O2), BSA (5%), FFA (200 μM), lactate (25 mM) and vehicle control for 24 h. (b~d) Protein stability of HIF1α in response to the treatment with hypoxia. (b), 200 μM FFA (c) and 25 mM lactate (d) for 24 h (n = 4, **P < 0.01). (e) Protein stability of HIF1α in response to the treatment with full or fractionated (>3 KD or <3 KD) serum from the 8-week ND or HFD-feeding mice. (n = 3, **P < 0.01). (f~h) Transcriptional activity of VEGF promoter in response to the treatment with hypoxia (f), 200 μM FFA (g) and 25 mM lactate (h) for 24 h (n = 3, *P < 0.05 and **P < 0.01). (i) Transcriptional activity of VEGF promoter in response to the treatment with full or fractionated (>3 KD or <3 KD) serum from the 8-week ND or HFD-feeding mice. (n = 3, **P < 0.01). Relative luc. activity: relative luciferase activity.
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f3: FFA and lactate potentiate HIF1α protein activity in mouse chondrocytes.(a) Immunoblotting assay of HIF1α in mouse primary chondrocytes treated with normal oxygen (Normoxia, 20% O2), low oxygen (hypoxia, 0.1% O2), BSA (5%), FFA (200 μM), lactate (25 mM) and vehicle control for 24 h. (b~d) Protein stability of HIF1α in response to the treatment with hypoxia. (b), 200 μM FFA (c) and 25 mM lactate (d) for 24 h (n = 4, **P < 0.01). (e) Protein stability of HIF1α in response to the treatment with full or fractionated (>3 KD or <3 KD) serum from the 8-week ND or HFD-feeding mice. (n = 3, **P < 0.01). (f~h) Transcriptional activity of VEGF promoter in response to the treatment with hypoxia (f), 200 μM FFA (g) and 25 mM lactate (h) for 24 h (n = 3, *P < 0.05 and **P < 0.01). (i) Transcriptional activity of VEGF promoter in response to the treatment with full or fractionated (>3 KD or <3 KD) serum from the 8-week ND or HFD-feeding mice. (n = 3, **P < 0.01). Relative luc. activity: relative luciferase activity.

Mentions: It’s well established that lactic acid is largely produced in hypoxia state, which increases stability and activity of HIF1α, a recently characterized enhancer of chronic inflammation in adipose tissue in obese mice1719. Specially, stearic acid and lactate-induced VEGF is a well-known transcriptional target of HIF1α20. Thus, we presumed that stearic acid and lactate might regulate the protein stability and transcriptional activity of HIF1α. As expected, similar to hypoxia, both stearic acid and lactate induced protein levels (Fig. 3a), protein stability (Fig. 3b~d) and transcription activity (Fig. 3f~h) of HIF1α in primary chondrocytes. Furthermore, we confirmed that metabolite fraction of serum from the HFD-feeding mice notably induced HIF1α protein stability (Fig. 3e) and transcription activity (Fig. 3i).


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 potentiate HIF1α protein activity in mouse chondrocytes.(a) Immunoblotting assay of HIF1α in mouse primary chondrocytes treated with normal oxygen (Normoxia, 20% O2), low oxygen (hypoxia, 0.1% O2), BSA (5%), FFA (200 μM), lactate (25 mM) and vehicle control for 24 h. (b~d) Protein stability of HIF1α in response to the treatment with hypoxia. (b), 200 μM FFA (c) and 25 mM lactate (d) for 24 h (n = 4, **P < 0.01). (e) Protein stability of HIF1α in response to the treatment with full or fractionated (>3 KD or <3 KD) serum from the 8-week ND or HFD-feeding mice. (n = 3, **P < 0.01). (f~h) Transcriptional activity of VEGF promoter in response to the treatment with hypoxia (f), 200 μM FFA (g) and 25 mM lactate (h) for 24 h (n = 3, *P < 0.05 and **P < 0.01). (i) Transcriptional activity of VEGF promoter in response to the treatment with full or fractionated (>3 KD or <3 KD) serum from the 8-week ND or HFD-feeding mice. (n = 3, **P < 0.01). Relative luc. activity: relative luciferase activity.
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Related In: Results  -  Collection

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f3: FFA and lactate potentiate HIF1α protein activity in mouse chondrocytes.(a) Immunoblotting assay of HIF1α in mouse primary chondrocytes treated with normal oxygen (Normoxia, 20% O2), low oxygen (hypoxia, 0.1% O2), BSA (5%), FFA (200 μM), lactate (25 mM) and vehicle control for 24 h. (b~d) Protein stability of HIF1α in response to the treatment with hypoxia. (b), 200 μM FFA (c) and 25 mM lactate (d) for 24 h (n = 4, **P < 0.01). (e) Protein stability of HIF1α in response to the treatment with full or fractionated (>3 KD or <3 KD) serum from the 8-week ND or HFD-feeding mice. (n = 3, **P < 0.01). (f~h) Transcriptional activity of VEGF promoter in response to the treatment with hypoxia (f), 200 μM FFA (g) and 25 mM lactate (h) for 24 h (n = 3, *P < 0.05 and **P < 0.01). (i) Transcriptional activity of VEGF promoter in response to the treatment with full or fractionated (>3 KD or <3 KD) serum from the 8-week ND or HFD-feeding mice. (n = 3, **P < 0.01). Relative luc. activity: relative luciferase activity.
Mentions: It’s well established that lactic acid is largely produced in hypoxia state, which increases stability and activity of HIF1α, a recently characterized enhancer of chronic inflammation in adipose tissue in obese mice1719. Specially, stearic acid and lactate-induced VEGF is a well-known transcriptional target of HIF1α20. Thus, we presumed that stearic acid and lactate might regulate the protein stability and transcriptional activity of HIF1α. As expected, similar to hypoxia, both stearic acid and lactate induced protein levels (Fig. 3a), protein stability (Fig. 3b~d) and transcription activity (Fig. 3f~h) of HIF1α in primary chondrocytes. Furthermore, we confirmed that metabolite fraction of serum from the HFD-feeding mice notably induced HIF1α protein stability (Fig. 3e) and transcription activity (Fig. 3i).

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