Cilostazol inhibits insulin-stimulated expression of sterol regulatory binding protein-1c via inhibition of LXR and Sp1

• Published in: Experimental & molecular medicine 2014, 46(0), , pp.1-8
• Main Authors: 정윤아, 김희경, 배기현, 서혜영, 김혜순, 장병국, 정권수, 이인규, 박근규, 김미경
• Format: Article
• Language: English
• Subjects: 생화학
• ISSN: 1226-3613; 2092-6413

Hepatic steatosis is common in obese individuals with hyperinsulinemia and is an important hepatic manifestation of metabolicsyndrome. Sterol regulatory binding protein-1c (SREBP-1c) is a master regulator of lipogenic gene expression in the liver. Hyperinsulinemia induces transcription of SREBP-1c via activation of liver X receptor (LXR) and specificity protein 1 (Sp1). Cilostazol is an antiplatelet agent that prevents atherosclerosis and decreases serum triglyceride levels. However, little is knownabout the effects of cilostazol on hepatic lipogenesis. Here, we examined the role of cilostazol in the regulation of SREBP-1ctranscription in the liver. The effects of cilostazol on the expression of SREBP-1c and its target genes in response to insulin oran LXR agonist (T0901317) were examined using real-time RT-PCR and western blot analysis on cultured hepatocytes. Toinvestigate the effect of cilostazol on SREBP-1c at the transcriptional level, transient transfection reporter assays andelectrophoretic mobility shift assays (EMSAs) were performed. Cilostazol inhibited insulin-induced and LXR-agonist-inducedexpression of SREBP-1c and its downstream targets, acetyl-CoA carboxylase and fatty acid synthase, in cultured hepatocytes. Cilostazol also inhibited activation of the SREBP-1c promoter by insulin, T0901317 and Sp1 in a luciferase reporter assay. EMSA analysis showed that cilostazol inhibits SREBP-1c expression by repressing the binding of LXR and Sp1 to the promoterregion. These results indicate that cilostazol inhibits insulin-induced hepatic SREBP-1c expression via the inhibition of LXRand Sp1 activity and that cilostazol is a negative regulator of hepatic lipogenesis. KCI Citation Count: 2