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

Malmgren, Siri, Spegel, Peter, Danielsson, Anders P. H., Nagorny, Cecilia L., Andersson, Lotta E., Nitert, Marloes Dekker, Ridderstrale, Martin, Mulder, Hindrik and Ling, Charlotte (2013) Coordinate changes in histone modifications, mRNA levels, and metabolite profiles in clonal INS-1 832/13 beta-cells accompany functional adaptations to lipotoxicity. Journal of Biological Chemistry, 288 17: 11973-11987. doi:10.1074/jbc.M112.422527


Author Malmgren, Siri
Spegel, Peter
Danielsson, Anders P. H.
Nagorny, Cecilia L.
Andersson, Lotta E.
Nitert, Marloes Dekker
Ridderstrale, Martin
Mulder, Hindrik
Ling, Charlotte
Title Coordinate changes in histone modifications, mRNA levels, and metabolite profiles in clonal INS-1 832/13 beta-cells accompany functional adaptations to lipotoxicity
Formatted title
Coordinate changes in histone modifications, mRNA levels, and metabolite profiles in clonal INS-1 832/13 β-cells accompany functional adaptations to lipotoxicity
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
1083-351X
Publication date 2013-04-26
Year available 2013
Sub-type Article (original research)
DOI 10.1074/jbc.M112.422527
Open Access Status DOI
Volume 288
Issue 17
Start page 11973
End page 11987
Total pages 15
Place of publication Bethesda, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Collection year 2014
Language eng
Formatted abstract
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 was increased, and oxygen consumption was impaired. Halting exposure of the clonal INS-1 832/13 β-cells to palmitate 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.
Keyword Induced insulin-secretion
Endoplasmic-reticulum stress
Human pancreatic-islets
Fatty-acid cycle
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
Official 2014 Collection
School of Medicine Publications
 
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