title: RNA-binding protein HuD reduces triglyceride production in pancreatic β cells by enhancing the expression of insulin-induced gene 1.
abstract: Although triglyceride (TG) accumulation in the pancreas leads to β-cell dysfunction and raises the chance to develop metabolic disorders such as type 2 diabetes (T2DM), the molecular mechanisms whereby intracellular TG levels are regulated in pancreatic β cells have not been fully elucidated. Here, we present evidence that the RNA-binding protein HuD regulates TG production in pancreatic β cells. Mouse insulinoma βTC6 cells stably expressing a small hairpin RNA targeting HuD (shHuD) (βTC6-shHuD) contained higher TG levels compared to control cells. Moreover, downregulation of HuD resulted in a decrease in insulin-induced gene 1 (INSIG1) levels but not in the levels of sterol regulatory element-binding protein 1c (SREBP1c), a key transcription factor for lipid production. We identified Insig1 mRNA as a direct target of HuD by using ribonucleoprotein immunoprecipitation (RIP) and biotin pulldown analyses. By associating with the 3'-untranslated region (3'UTR) of Insig1 mRNA, HuD promoted INSIG1 translation; accordingly, HuD downregulation reduced while ectopic HuD expression increased INSIG1 levels. We further observed that HuD downregulation facilitated the nuclear localization of SREBP1c, thereby increasing the transcriptional activity of SREBP1c and the expression of target genes involved in lipogenesis; likewise, we observed lower INSIG1 levels in the pancreatic islets of HuD-null mice. Taken together, our results indicate that HuD functions as a novel repressor of lipid synthesis in pancreatic β cells.
authors.affiliation: Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
authors.forename: Chongtae
authors.initials: C
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
authors.forename: Heejin
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
authors.forename: Hoin
authors.initials: H
authors.lastname: Kang
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon 443-749, South Korea.
authors.forename: Jung Jae
authors.initials: JJ
authors.lastname: Shin
authors.affiliation: Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
authors.forename: Hyosun
authors.initials: H
authors.lastname: Tak
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon 443-749, South Korea.
authors.forename: Wook
authors.initials: W
authors.lastname: Kim
authors.affiliation: Laboratory of Genetics, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
authors.forename: Myriam
authors.initials: M
authors.lastname: Gorospe
authors.affiliation: Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea; Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea. Electronic address: leeek@catholic.ac.kr.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Lee
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000067779:ELAV-Like Protein 4 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D000067779:ELAV-Like Protein 4; C498011:Elavl4 protein, mouse; C108626:INSIG1 protein, human; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides
keywords: HuD; INSIG1; RNA-binding protein; SREBP1c; Triglyceride