Exp Mol Med.  2014 Jan;46(1):e73. 10.1038/emm.2013.143.

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

• Jung YA
• Kim HK
• Bae KH
• Seo HY
• Kim HS
• Jang BK
• Jung GS
• Lee IK
• Kim MK
• Park KG

• KMID: 2155338
• DOI: http://doi.org/10.1038/emm.2013.143

Abstract

Hepatic steatosis is common in obese individuals with hyperinsulinemia and is an important hepatic manifestation of metabolic syndrome. 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 known about the effects of cilostazol on hepatic lipogenesis. Here, we examined the role of cilostazol in the regulation of SREBP-1c transcription in the liver. The effects of cilostazol on the expression of SREBP-1c and its target genes in response to insulin or an LXR agonist (T0901317) were examined using real-time RT-PCR and western blot analysis on cultured hepatocytes. To investigate the effect of cilostazol on SREBP-1c at the transcriptional level, transient transfection reporter assays and electrophoretic mobility shift assays (EMSAs) were performed. Cilostazol inhibited insulin-induced and LXR-agonist-induced expression 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 promoter region. These results indicate that cilostazol inhibits insulin-induced hepatic SREBP-1c expression via the inhibition of LXR and Sp1 activity and that cilostazol is a negative regulator of hepatic lipogenesis.

Keyword

cilostazol; lipogenesis; LXR; Sp1; SREBP-1c

MeSH Terms

Animals
Cells, Cultured
Hep G2 Cells
Hepatocytes/drug effects/*metabolism
Humans
Hydrocarbons, Fluorinated/pharmacology
Insulin/pharmacology
Lipogenesis
Mice
Mice, Inbred C57BL
Orphan Nuclear Receptors/agonists/*metabolism
Promoter Regions, Genetic
Protein Binding
Rats
Sp1 Transcription Factor/*metabolism
Sterol Regulatory Element Binding Protein 1/genetics/*metabolism
Sulfonamides/pharmacology
Tetrazoles/*pharmacology
Hydrocarbons, Fluorinated
Insulin
Orphan Nuclear Receptors
Sp1 Transcription Factor
Sterol Regulatory Element Binding Protein 1
Sulfonamides
Tetrazoles