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(Received for publication, August 30, 1996, and in revised form, October 30, 1996)
From the Fatty acids are important metabolic substrates
for the pancreatic
Volume 272, Number 3,
Issue of January 17, 1997
pp. 1659-1664
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
-Cell Line INS-1
,
Département de Biochimie
Médicale, Centre Médical Universitaire, University of
Geneva, 1211 Geneva 4, Switzerland, the ¶ Molecular Nutrition
Unit, Department of Nutrition, University of Montreal, Montreal QC,
H3C 3J7 Canada, and the ** Department of Internal Medicine,
University of Texas, Southwestern Medical Center, Dallas, Texas
25235
-cell, and long term exposure of pancreatic
islets to elevated concentrations of fatty acids results in an
alteration of glucose-induced insulin secretion. Previous work
suggested that exaggerated fatty acid oxidation may be implicated in
this process by a mechanism requiring changes in metabolic enzyme
expression. We have therefore studied the regulation of carnitine
palmitoyltransferase I (CPT I) gene expression by fatty acids in the
pancreatic -cell line INS-1 since this enzyme catalyzes the limiting
step of fatty acid oxidation in various tissues. Palmitate, oleate, and
linoleate (0.35 mM) elicited a 4-6-fold increase in CPT I
mRNA. The effect was dose-dependent and was similar for
saturated and unsaturated fatty acids. It was detectable after 1 h
and reached a maximum after 3 h. The induction of CPT I mRNA
by fatty acids did not require their oxidation, and 2-bromopalmitate, a
nonoxidizable fatty acid, increased CPT I mRNA to the same extent
as palmitate. The induction was not prevented by cycloheximide
treatment of cells indicating that it was mediated by pre-existing
transcription factors. Neither glucose nor pyruvate and various
secretagogues had a significant effect except glutamine (7 mM) which slightly induced CPT I mRNA. The half-life of
the CPT I transcript was unchanged by fatty acids, and nuclear run-on
analysis showed a rapid (less than 45 min) and pronounced
transcriptional activation of the CPT I gene by fatty acids. The
increase in CPT I mRNA was followed by a 2-3-fold increase in CPT
I enzymatic activity measured in isolated mitochondria. The increase in
activity was time-dependent, detectable after 4 h, and
close to maximal after 24 h. Fatty acid oxidation by INS-1 cells,
measured at low glucose, was also 2-3-fold higher in cells cultured
with fatty acid in comparison with control cells. Long term exposure of
INS-1 cells to fatty acid was associated with elevated secretion of
insulin at a low (5 mM) concentration of glucose and a
decreased effect of higher glucose concentrations. It also resulted in
a decreased oxidation of glucose. The results indicate that the CPT I
gene is an early response gene induced by fatty acids at the
transcriptional level in - (INS-1) cells. It is suggested that
exaggerated fatty acid oxidation caused by CPT-1 induction is
implicated in the process whereby fatty acids alter glucose-induced
insulin secretion.
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