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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

Increased production of proinflammatory cytokines and VEGF in the plasma and chondrocytes in high fat diet (HFD)-feeding mice.(a~d) levels of plasma IL-6 (a), TNF-α (b), IL-1β (c) and VEGF (d) in the C57BL/6 male mice fed with a normal diet (ND) or HFD for 8 weeks. (n = 5, **P < 0.01). (e~h) Relative mRNA expression of IL-6 (e), TNF-α (f), IL-1β (g) and VEGF (h) in the chondrocytes isolated from the 8-week ND or HFD-feeding mice. (n = 5, **P < 0.01).
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f1: Increased production of proinflammatory cytokines and VEGF in the plasma and chondrocytes in high fat diet (HFD)-feeding mice.(a~d) levels of plasma IL-6 (a), TNF-α (b), IL-1β (c) and VEGF (d) in the C57BL/6 male mice fed with a normal diet (ND) or HFD for 8 weeks. (n = 5, **P < 0.01). (e~h) Relative mRNA expression of IL-6 (e), TNF-α (f), IL-1β (g) and VEGF (h) in the chondrocytes isolated from the 8-week ND or HFD-feeding mice. (n = 5, **P < 0.01).

Mentions: To verify the positive correlation between obesity and OA, we set up an obese mouse model by feeding the mice with a HFD for 8 weeks. Consistent with previous studies5618, HFD induced a low grade inflammation state, characterized by elevated production of IL-6 (Fig. 1a), TNF-α (Fig. 1b) and IL-1β (Fig. 1c) in plasma. Meanwhile, plasma VEGF, a well-documented risk factor of OA, was also induced by HFD (Fig. 1d). Further, the expression pattern of chondrocyte cytokines was identical with the aforementioned ones in plasma (Fig. 1e~h). These results indicated that the HFD induced a low grade inflammation in the mouse cartilages. However, the 8 weeks of HFD-feeding mice didn’t display any signs of osteoarthritis in histomorphology (see Supplementary Fig. S1).


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)

Increased production of proinflammatory cytokines and VEGF in the plasma and chondrocytes in high fat diet (HFD)-feeding mice.(a~d) levels of plasma IL-6 (a), TNF-α (b), IL-1β (c) and VEGF (d) in the C57BL/6 male mice fed with a normal diet (ND) or HFD for 8 weeks. (n = 5, **P < 0.01). (e~h) Relative mRNA expression of IL-6 (e), TNF-α (f), IL-1β (g) and VEGF (h) in the chondrocytes isolated from the 8-week ND or HFD-feeding mice. (n = 5, **P < 0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Increased production of proinflammatory cytokines and VEGF in the plasma and chondrocytes in high fat diet (HFD)-feeding mice.(a~d) levels of plasma IL-6 (a), TNF-α (b), IL-1β (c) and VEGF (d) in the C57BL/6 male mice fed with a normal diet (ND) or HFD for 8 weeks. (n = 5, **P < 0.01). (e~h) Relative mRNA expression of IL-6 (e), TNF-α (f), IL-1β (g) and VEGF (h) in the chondrocytes isolated from the 8-week ND or HFD-feeding mice. (n = 5, **P < 0.01).
Mentions: To verify the positive correlation between obesity and OA, we set up an obese mouse model by feeding the mice with a HFD for 8 weeks. Consistent with previous studies5618, HFD induced a low grade inflammation state, characterized by elevated production of IL-6 (Fig. 1a), TNF-α (Fig. 1b) and IL-1β (Fig. 1c) in plasma. Meanwhile, plasma VEGF, a well-documented risk factor of OA, was also induced by HFD (Fig. 1d). Further, the expression pattern of chondrocyte cytokines was identical with the aforementioned ones in plasma (Fig. 1e~h). These results indicated that the HFD induced a low grade inflammation in the mouse cartilages. However, the 8 weeks of HFD-feeding mice didn’t display any signs of osteoarthritis in histomorphology (see Supplementary Fig. S1).

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