DHA reduces inflammation by inhibiting FoxO1 through GPR120

• Main Authors: Chia-Ching Chang, 張家菁
• Other Authors: Shih-Torng Ding
• Format: Others
• Language: en_US
• Published: 2011
• Online Access: http://ndltd.ncl.edu.tw/handle/62262548408761623988

碩士 === 國立臺灣大學 === 動物科學技術學研究所 === 99 === Obesity nowdays considered as a chronic, low-grade subclinical inflammatory state in association with metabolic diseases. Relaease and production of proinflammatory adipokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1β are greatly enhanced in the adipose tissue due to excessive lipid accumulation. Docosahexaenoic acids (DHA) belongs one of the essential ω-3 polyunsaturated fatty acids for mammals. It has been shown the activation of the NF-κB, a key proinflammatory transcription factor through G-protein-coupled receptor 120 (GPR120). The subclass of forkhead transcription factors O (FoxOs), FoxO1, plays an important role in inflammation. Phosphorylation of FoxO1 by phosphoinositide 3-kinase (PI3K) and protein kinase B (PKB, Akt) to change the subcellular location of FoxO1 from nucleus into cytosol diminish FoxO1 binding on its target genes such as IL-1β and MCP-1. Hence, it is plausible that DHA can down-regulate FoxO1 expression by promoting AKT activation through GPR120. The human monocytic cell line THP-1 cells were subsequently treated with different dose of DHA ( 50, 100, 150 or 200 μM ) with or without palmitic acids (200 μM PA) co-culture for 6 or 24 hr. Expression of FoxO1, IL-1β, MCP-1, and TNF-α was increased by PA treatment. The increase of FoxO1 expression by PA was suppressed in presene of 100 μM DHA under short-term or long-term treatment. Expression of IL-1β was inhibited by 50, 100, 150 and 200 μM DHA under long-term treatment. Expression of TNF-α and MCP-1 induced by PA under short- or long-term treatment were decreased by 100 or 150 μM DHA treatment. DHA promoted AKT activation, particularly at 100 μM level in either presence or absence of PA. Expression of at protein level was increased by PA treatment but inhibited by DHA. Treatment of DHA also increased FoxO1 phosphorylation in a dose dependent fashion. In order to confirm the relationship between DHA and PI3K/AKT pathway, PI3K inhibitor, LY294002, was used in the study. Palmitic acid-induced expression of FoxO1 and TNF-α was aupressed in presence of DHA and such effect was diminished by LY294002, indicating that DHA may reduce FoxO1 expression through the PI3K/AKT pathway. Moreover, the PA-induced expression of FoxO1, IL-1β, TNF-α and MCP-1 was decreased by DHA or GW9508, an agonist of GPR120. Addition of DHA and GW9508 together, however, did not enhance their inhibitory effect on FoxO1 and proinflammatory gene expressions as compared with DHA or GW9508 treatment alone. By using small interfering RNAs with a lentivirus system, GPR120 expreesion was reduced to 30%. Expression FoxO1 was induced by PA in null-vector or GPR120 RNAi treated cells. Treatment DHA blunted the elevation of FoxO1, TNF-α and IL-1β expression by PA induction in cells with null-vector treatment but not GPR120 RNAi cells. These results suggested expression of FoxO1 is reduced by DHA act through PI3K/AKT signaling and GPR120 pathway. Treatment of DHA increased AKT activation similar to that of GPR120 RNAi transfected cells. Transfection with GPR120 RNAi suppressed both AKT transcript and phosphorylation level. Palmitic acid treatment suppressed but DHA treatment increased FoxO1phosphorylation transfected GPR120 RNAi. In general, GPR120 RNAi transfection suppress p-FoxO1/FoxO1 ratio. The results suggested that DHA regulates phosphorylation of AKT and FoxO1 is mediated through GPR120 signaling. In conclusion, the beneficial role of DHA may partially act through down-regulation of FoxO1 functions though GPR120 and/or PI3K pathway, which reduce in such inflammatory factor gene expressions. This study indicates that DHA is provided with reducing inflammation which induces by saturated fatty acids.