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Coordinate changes in histone modifications, mRNA levels and metabolite profiles in clonal INS-1 832/13 β-cells accompany functional adaptations to lipotoxicity.

Author:
  • Siri Malmgren
  • Peter Spégel
  • Anders Danielsson
  • Cecilia Nagorny
  • Lotta Andersson
  • Marloes Dekker Nitert
  • Martin Ridderstråle
  • Hindrik Mulder
  • Charlotte Ling
Publishing year: 2013
Language: English
Pages: 11973-11987
Publication/Series: Journal of Biological Chemistry
Volume: 288
Issue: 17
Document type: Journal article
Publisher: ASBMB

Abstract english

Lipotoxicity is a presumed pathogenetic process whereby elevated circulating and stored lipids in Type 2 Diabetes cause pancreatic β-cell failure. To resolve the underlying molecular mechanisms, we exposed clonal INS-1 832/13 β-cells to palmitate for 48 h. We observed elevated basal insulin secretion but impaired glucose-stimulated insulin secretion in palmitate-exposed cells. Glucose utilization was unchanged, palmitate oxidation increased, and oxygen consumption impaired. Removal of palmitate from the clonal INS-1 832/13 β-cells largely recovered all of the lipid-induced functional changes. Metabolite profiling revealed profound but reversible increases in cellular lipids. Glucose-induced increases in tricarboxylic acid cycle intermediates were attenuated by exposure to palmitate. Analysis of gene expression by microarray showed increased expression of 982 genes and decreased expression of 1032 genes after exposure to palmitate. Increases were seen in pathways for steroid biosynthesis, cell cycle, fatty acid metabolism, DNA replication, and biosynthesis of unsaturated fatty acids; decreases occurred in the aminoacyl-tRNA-synthesis pathway. The activity of histone-modifying enzymes and histone modifications of differentially expressed genes were reversibly altered upon exposure to palmitate. Thus, Insig1, Lss, Peci, Idi1, Hmgcs1 and Casr were subject to epigenetic regulation. Our analyses demonstrate that coordinate changes in histone modifications, mRNA levels and metabolite profiles accompanied functional adaptations of clonal β-cells to lipotoxicity. It is highly likely that these changes are pathogenetic, accounting for loss of glucose responsiveness and perturbed insulin secretion.

Keywords

  • Endocrinology and Diabetes

Other

Published
  • Molecular Metabolism
  • Epigenetics and Diabetes
  • Clinical Obesity
  • ISSN: 1083-351X
Peter Spegel
E-mail: peter [dot] spegel [at] chem [dot] lu [dot] se

Researcher

Centre for Analysis and Synthesis

1

Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00