title: Effects of palmitate on genome-wide mRNA expression and DNA methylation patterns in human pancreatic islets.
abstract: BACKGROUND
  Circulating free fatty acids are often elevated in patients with type 2 diabetes (T2D) and obese individuals. Chronic exposure to high levels of saturated fatty acids has detrimental effects on islet function and insulin secretion. Altered gene expression and epigenetics may contribute to T2D and obesity. However, there is limited information on whether fatty acids alter the genome-wide transcriptome profile in conjunction with DNA methylation patterns in human pancreatic islets. To dissect the molecular mechanisms linking lipotoxicity to impaired insulin secretion, we investigated the effects of a 48 h palmitate treatment in vitro on genome-wide mRNA expression and DNA methylation patterns in human pancreatic islets.
  
  
  METHODS
  Genome-wide mRNA expression was analyzed using Affymetrix GeneChip(®) Human Gene 1.0 ST whole transcript-based array (n = 13) and genome-wide DNA methylation was analyzed using Infinium HumanMethylation450K BeadChip (n = 13) in human pancreatic islets exposed to palmitate or control media for 48 h. A non-parametric paired Wilcoxon statistical test was used to analyze mRNA expression. Apoptosis was measured using Apo-ONE(®) Homogeneous Caspase-3/7 Assay (n = 4).
  
  
  RESULTS
  While glucose-stimulated insulin secretion was decreased, there was no significant effect on apoptosis in human islets exposed to palmitate. We identified 1,860 differentially expressed genes in palmitate-treated human islets. These include candidate genes for T2D, such as TCF7L2, GLIS3, HNF1B and SLC30A8. Additionally, genes in glycolysis/gluconeogenesis, pyruvate metabolism, fatty acid metabolism, glutathione metabolism and one carbon pool by folate were differentially expressed in palmitate-treated human islets. Palmitate treatment altered the global DNA methylation level and DNA methylation levels of CpG island shelves and shores, 5'UTR, 3'UTR and gene body regions in human islets. Moreover, 290 genes with differential expression had a corresponding change in DNA methylation, for example, TCF7L2 and GLIS3. Importantly, out of the genes differentially expressed due to palmitate treatment in human islets, 67 were also associated with BMI and 37 were differentially expressed in islets from T2D patients.
  
  
  CONCLUSIONS
  Our study demonstrates that palmitate treatment of human pancreatic islets gives rise to epigenetic modifications that together with altered gene expression may contribute to impaired insulin secretion and T2D.
authors: Elin
authors: E
authors: Hall
authors: Petr
authors: P
authors: Volkov
authors: Tasnim
authors: T
authors: Dayeh
authors: Karl
authors: K
authors: Bacos
authors: Tina
authors: T
authors: Rönn
authors: Marloes Dekker
authors: MD
authors: Nitert
authors: Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, CRC, Lund University, Scania University Hospital, Malmö, Sweden. charlotte.ling@med.lu.se.
authors: Charlotte
authors: C
authors: Ling
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects*; D055106:Genome-Wide Association Study; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D050356:Lipid Metabolism; D009765:Obesity / Q000209:etiology; D010168:Palmitates / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: D007328:Insulin; D010168:Palmitates; D012333:RNA, Messenger; D053148:Caspase 3; D053179:Caspase 7; D005947:Glucose