Coordinate changes in histone modifications, mRNA levels and metabolite profiles in clonal INS-1 832/13 β-cells accompany functional adaptations to lipotoxicity.
Malmgren, Siri LU ; Spégel, Peter LU ; Danielsson, Anders LU ; Nagorny, Cecilia LU ; Andersson, Lotta LU ; Dekker Nitert, Marloes LU ; Ridderstråle, Martin LU ; Mulder, Hindrik LU
and Ling, Charlotte
LU
(2013)
In Journal of Biological Chemistry
288(17).
p.11973-11987
- 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 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... (More)
- 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3628326
- author
- Malmgren, Siri
LU
; Spégel, Peter
LU
; Danielsson, Anders
LU
; Nagorny, Cecilia
LU
; Andersson, Lotta
LU
; Dekker Nitert, Marloes
LU
; Ridderstråle, Martin
LU
; Mulder, Hindrik
LU
and Ling, Charlotte
LU
- organization
- publishing date
- 2013
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Biological Chemistry
- volume
- 288
- issue
- 17
- pages
- 11973 - 11987
- publisher
- American Society for Biochemistry and Molecular Biology
- external identifiers
-
- wos:000318157600032
- pmid:23476019
- scopus:84876934840
- pmid:23476019
- ISSN
- 1083-351X
- DOI
- 10.1074/jbc.M112.422527
- language
- English
- LU publication?
- yes
- id
- 96d0a875-9b53-41d0-bebb-040b57a6d8f5 (old id 3628326)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/23476019?dopt=Abstract
- date added to LUP
- 2016-04-01 10:21:59
- date last changed
- 2024-02-21 15:02:00
@article{96d0a875-9b53-41d0-bebb-040b57a6d8f5,
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 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.}},
author = {{Malmgren, Siri and Spégel, Peter and Danielsson, Anders and Nagorny, Cecilia and Andersson, Lotta and Dekker Nitert, Marloes and Ridderstråle, Martin and Mulder, Hindrik and Ling, Charlotte}},
issn = {{1083-351X}},
language = {{eng}},
number = {{17}},
pages = {{11973--11987}},
publisher = {{American Society for Biochemistry and Molecular Biology}},
series = {{Journal of Biological Chemistry}},
title = {{Coordinate changes in histone modifications, mRNA levels and metabolite profiles in clonal INS-1 832/13 β-cells accompany functional adaptations to lipotoxicity.}},
url = {{http://dx.doi.org/10.1074/jbc.M112.422527}},
doi = {{10.1074/jbc.M112.422527}},
volume = {{288}},
year = {{2013}},
}