Cilostazol inhibits insulin-stimulated expression of sterol regulatory binding protein-1c via inhibition of LXR and Sp1.
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.
Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea.
Yun-A
YA
Jung
Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea.
Hee Kyoung
HK
Kim
Division of Endocrinology and Metabolism, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea.
Kwi-Hyun
KH
Bae
Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea.
Hye-Young
HY
Seo
Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea.
Hye-Soon
HS
Kim
Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea.
Byoung Kuk
BK
Jang
Division of Endocrinology and Metabolism, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea.
Gwon-Soo
GS
Jung
Division of Endocrinology and Metabolism, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea.
In-Kyu
IK
Lee
Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea.
Mi-Kyung
MK
Kim
Division of Endocrinology and Metabolism, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea.
Keun-Gyu
KG
Park
D000818:Animals; D002478:Cells, Cultured; D000077407:Cilostazol; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D050155:Lipogenesis; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051381:Rats; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000077407:Cilostazol; D006845:Hydrocarbons, Fluorinated; D007328:Insulin; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D016329:Sp1 Transcription Factor; D051780:Sterol Regulatory Element Binding Protein 1; D013449:Sulfonamides; D013777:Tetrazoles; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides