二十二碳六烯酸藉由血漿澱粉酶A蛋白與四締素調控脂肪細胞脂質分解與堆積

Abstract

脂肪代謝相關疾病，例如:胰島素阻抗、糖尿病以及心血管疾病嚴重威脅人類健康,而N-3多不飽合脂肪酸,特別是docosahexaenoic acid (DHA)被發現對這些疾病有療效，但其中的作用機制尚未被發覺。先前的研究顯示血液澱粉酶A (SAA)參與DHA在之下脂質代謝的調控，於是我們率先先設計實驗闡明其中的機制。結果顯示，在初代培養的人類脂肪細胞(PHA), DHA處理則增加SAA基因及其它相關脂質代謝基因的表現。另外，SAA重組蛋白的處理,抑制PPARγ及脂質生成基因表現，並且提升脂質分解基因的表現,例如hormone sensitive lipase (HSL)，同時伴隨甘油自脂肪細胞釋出的提高。我們更進一步發現，SAA的處理，降低覆膜在油滴表面的perilipin基因表現。此結果說明，DHA和SAA部份增加HSL的基因表現並透過降低perilipin來影響脂解作用。在另一個研究中，利用二維電泳的技術，我們發現一個會與plasminogen結合的蛋白；四締素（tetranectin ；TN)，為一種自脂肪細胞外泌的脂肪細胞激素。基因表現分析中顯示，在人類脂肪組織中，TN的表現量與身體質量指數(BMI)和脂質生合成呈正比。利用腺病毒大量表現TN在PHA中，可提高脂質生成相關基因表現及油滴在脂肪細胞中堆積。同樣利用腺病毒感染PHA，降低TN表現的實驗中，則無以上的現象。活體實驗中顯示，相較於對照組，高脂餵飼的小鼠脂肪組織中有大量TN表現。小鼠在DHA的餵飼後，TN表現則顯著受到抑制。綜合以上結果，顯示DHA可調控脂解因子SAA表現上升及並降低促進脂質生成的TN表現，進而調整脂肪組織中的脂質代謝，有益於改善肥胖。從此成果中，可做為未來發展治療肥胖及相關疾病的方向。

Obesity is highly associated with insulin resistance, diaabetes and cardiovascular diseases, and thereby greatly impacts human health. n-3 polyunsaturated fatty acids, specifically docosahexaenoic acid (DHA), has beneficial effects on human health, but the underlying mechanisms remain elusive. Based on our previous studies that serum amyloid A protein (SAA) is involved in DHA’s regulation of lipid metabolisms, we then conducted a serious of studies to elucidate the underlying mechanism. Promoted SAA and lipid metabolism-associated gene expression in human adipocytes results showed that treating the primary human adipocytes (PHA) with DHA increases the gene expression of SAA and those genes associated with lipid metabolism. Moreover, addition of recombinant SAA inhibited the expression of peroxisome proliferator-activated receptor γ and lipogenic genes, but enhanced lipolytic gene expression such as hormone sensitive lipase (HSL) in PHA, in association with increased glycerol release into the medium. We also found that expression of perilipin, a lipid droplet-coating protein, was decreased by hSAA1 treatment. These results suggest that the lipolytic effects of DHA and SAA are, at least partially, mediated by upregulation of HSL and perilipin downregulation. Using 2D PAGE technique, a plasminogen -kind protein, tetranectin (TN) was identified as a secretory adipocytokin from PHA. In human adipose tissue, expression of TN is positively correlated with body mass index, as well as adipogenesis. Lentiviral overexpression of TN in PHA increased the expression of lipogenic genes and lipid accumulation, which were blocked by lentiviral knockdown of TN. Finally, we found that TN expression was elevated in the adipose tissues of mice fed with high-fat diet fed, but was diminished by DHA treatment. Taken together, our results suggest that DHA exerts beneficial effects on obesity by up-regulating a lipolytic factor, SAA expression, yet down-regulating lipogenic TN, to modulate lipid metabolism in the adipose tissue. The results gained from the study may shed lights for future development of better therapeutic approaches in obesity and related diseases.