Docosahexaenoic acid inhibits insulin-induced activation of sterol regulatory-element binding protein 1 and cyclooxygenase-2 expression through upregulation of SIRT1 in human colon epithelial cells
Docosahexaenoic acid inhibits insulin-induced activation of sterol regulatory-element binding protein 1 and cyclooxygenase-2 expression through upregulation of SIRT1 in human colon epithelial cells
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DOI：
10.1016/j.bcp.2014.08.030
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发表时间：
2014-11-01
影响因子：
5.8
通讯作者：
Surh, Young-Joon
中科院分区：
文献类型：
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作者：
Song, Na-Young;Na, Hye-Kyung;Surh, Young-Joon
来自临床和人群研究的多条令人信服的证据支持高胰岛素血症通常伴随肥胖相关的胰岛素不敏感性促进结肠癌发生。胰岛素可以乙酰化，从而激活固醇调节元件结合蛋白1（SREBP-1），这是一种负责脂肪生成相关基因表达的主要转录因子。此外，SREBP-1上调环氧化酶-2（考克斯-2），其是炎症信号传导中的关键参与者。二十二碳六烯酸（DHA）是一种代表性的ω-3多不饱和脂肪酸，已知其对SREBP-1具有负调节作用，但其分子机制尚未完全阐明。这促使我们研究DHA是否可以抑制胰岛素诱导的SREBP-1和考克斯-2表达的激活，在其对肥胖诱导的炎症和癌变的潜在保护作用的背景下。SIRT 1是一种NAD（+）依赖性的组蛋白/非组蛋白脱乙酰酶，已报道通过SREBP-1转录因子的脱乙酰化来抑制该转录因子介导的细胞内信号传导。我们发现DHA诱导CCD 841 CoN人结肠上皮细胞中SIRT 1的表达。DHA消除了胰岛素诱导的乙酰化以及SREBP-1和考克斯-2表达上调。DHA对胰岛素诱导的CCD 841 CoN细胞迁移也有抑制作用。DHA介导的这些作用通过SIRT 1的药理学抑制而减弱。高胰岛素血症或胰岛素抵抗被认为与肥胖相关的炎症有关。遗传性肥胖（ob/ob）小鼠的结肠SREBP-1和考克斯-2表达水平均高于正常瘦小鼠。同样，与周围正常组织相比，SREBP-1和考克斯-2在人结肠肿瘤标本中的表达升高。总之，DHA可通过上调SIRT 1抑制胰岛素诱导的SREBP-1活化和考克斯-2表达，从而预防肥胖相关炎症和结肠癌发生。(C)2014爱思唯尔公司All rights reserved.
Multiple lines of compelling evidence from clinical and population-based studies support that hyperinsulinemia often accompanying obesity-associated insulin insensitivity promotes colon carcinogenesis. Insulin can acetylate, thereby activating sterol regulator element-binding protein 1 (SREBP-1), a prime transcription factor responsible for expression of genes involved in lipogenesis. Moreover, SREBP-1 upregulates cyclooxygenase-2 (COX-2), a key player in inflammatory signaling. Docosahexaenoic acid (DHA), a representative omega-3 polyunsaturated fatty acid, has been known to negatively regulate SREBP-1, but the underlying molecular mechanism is not fully clarified yet. This prompted us to investigate whether DHA could inhibit insulin-induced activation of SREBP-1 and COX-2 expression in the context of its potential protective effect on obesity-induced inflammation and carcinogenesis. SIRT1, a NAD(+)-dependent histone/non-histone protein deacetylase, has been reported to inhibit intracellular signaling mediated by SREBP-1 through deacetylation of this transcription factor. We found that DHA induced SIRT1 expression in CCD841CoN human colon epithelial cells. DHA abrogated insulin-induced acetylation as well as expression of SREBP-1 and COX-2 upregulation. Insulin-induced stimulation of CCD841CoN cell migration was also inhbited by DHA. These effects mediated by DHA were attenuated by pharmacologic inhibition of SIRT1. Hyperinsulinemia or insulin resistance is considered to be associated with obesity-associated inflammation. Genetically obese (ob/ob)) mice showed higher colonic expression levels of both SREBP-1 and COX-2 than did normal lean mice. Likewise, expression of SREBP-1 and COX-2 was elevated in human colon tumor specimens compared with surrounding normal tissues. In conclusion, DHA may protect against obesity-associated inflammation and colon carcinogenesis by suppressing insulin-induced activation of SREBP-1 and expression of COX-2 through up-regulation of SIRT1. (C) 2014 Elsevier Inc. All rights reserved.