title: Mediation of glucolipotoxicity in INS-1 rat insulinoma cells by small heterodimer partner interacting leucine zipper protein (SMILE).
abstract: Sustained elevations of glucose and free fatty acid concentration have deleterious effects on pancreatic beta cell function. One of the hallmarks of such glucolipotoxicity is a reduction in insulin gene expression, resulting from decreased insulin promoter activity. Sterol regulatory element binding protein-1c (SREBP-1c), a lipogenic transcription factor, is related to the development of beta cell dysfunction caused by elevated concentrations of glucose and free fatty acid. Small heterodimer partner (SHP) interacting leucine zipper protein (SMILE), also known as Zhangfei, is a novel protein which interacts with SHP that mediates glucotoxicity in INS-1 rat insulinoma cells. Treatment of INS-1 cells with high concentrations of glucose and palmitate increased SREBP-1c and SMILE expression, and decreased insulin gene expression. Adenovirus-mediated overexpression of SREBP-1c in INS-1 cells induced SMILE expression. Moreover, adenovirus-mediated overexpression of SMILE (Ad-SMILE) in INS-1 cells impaired glucose-stimulated insulin secretion as well as insulin gene expression. Ad-SMILE overexpression also inhibited the expression of beta-cell enriched transcription factors including pancreatic duodenal homeobox factor-1, beta cell E box transactivator 2 and RIPE3b1/MafA, in INS-1 cells. Finally, in COS-1 cells, expression of SMILE inhibited the insulin promoter activity induced by these same beta-cell enriched transcription factors. These results collectively suggest that SMILE plays an important role in the development of beta cell dysfunction induced by glucolipotoxicity.
authors.affiliation: Department of Internal Medicine, Research Institute of Aging and Metabolism, WCU Program, Kyungpook National University School of Medicine, Daegu, South Korea.
authors.forename: Kyeong-Min
authors.initials: KM
authors.lastname: Lee
authors.forename: Ye Jin
authors.initials: YJ
authors.lastname: Seo
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Kim
authors.forename: Hyun-Ae
authors.initials: HA
authors.lastname: Seo
authors.forename: Ji-Yun
authors.initials: JY
authors.lastname: Jeong
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.forename: Keun-Gyu
authors.initials: KG
authors.lastname: Park
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000819:agonists / Q000378:metabolism*; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005947:Glucose / Q000633:toxicity*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D010168:Palmitates / Q000633:toxicity*; D051381:Rats; D051780:Sterol Regulatory Element Binding Protein 1 / Q000819:agonists / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; C570110:Crebzf protein, rat; D007328:Insulin; D010168:Palmitates; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D005947:Glucose