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

Abstract

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 inhibited 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.

Keywords: Colon cancer; Cyclooxygenase-2; Docosahexaenoic acid; Hyperinsulinemia; Obesity; SIRT1; Sterol regulatory element-binding protein 1.