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Activation of acetyl-CoA carboxylase by a glutamate- and magnesium-sensitive protein phosphatase in the islet beta-cell.
- Source :
- Diabetes; Jul2001, Vol. 50 Issue 7, p1580-1587, 8p, 1 Diagram, 7 Graphs
- Publication Year :
- 2001
-
Abstract
- Acetyl-CoA carboxylase (ACC) catalyzes the formation of malonyl-CoA, a precursor in the biosynthesis of long-chain fatty acids, which have been implicated in physiological insulin secretion. The catalytic function of ACC is regulated by phosphorylation (inactive)-dephosphorylation (active). In this study we investigated whether similar regulatory mechanisms exist for ACC in the pancreatic islet beta-cell. ACC was quantitated in normal rat islets, human islets, and clonal beta-cells (HIT-15 or INS-1) using a [(14)C]bicarbonate fixation assay. In the beta-cell lysates, ACC was stimulated by magnesium in a concentration-dependent manner. Of all the dicarboxylic acids tested, only glutamate, albeit ineffective by itself, significantly potentiated magnesium-activated ACC in a concentration-dependent manner. ACC stimulation by glutamate and magnesium was maximally demonstrable in the cytosolic fraction; it was markedly reduced by okadaic acid (OKA) in concentrations (<50 nmol/l) that inhibited protein phosphatase 2A (PP2A). Furthermore, pretreatment of the cytosolic fraction with anti-PP2A serum attenuated the glutamate- and magnesium-mediated activation of ACC, thereby suggesting that ACC may be regulated by an OKA-sensitive PP2A-like enzyme. Streptavidin-agarose chromatography studies have indicated that glutamate- and magnesium-mediated effects on ACC are attributable to activation of ACC's dephosphorylation; this suggests that the stimulatory effects of glutamate and magnesium on ACC might involve activation of an OKA-sensitive PP2A-like enzyme that dephosphorylates and activates ACC. In our study, 5-amino-imidazolecarboxamide (AICA) riboside, a stimulator of AMP kinase, significantly inhibited glucose-mediated activation of ACC and insulin secretion from isolated beta-cells. Together, our data provide evidence for a unique regulatory mechanism for the activation of ACC in the pancreatic beta-cell, leading to the generation of physiological signals that may be relevant for physiological insulin secretion. [ABSTRACT FROM AUTHOR]
- Subjects :
- PHOSPHOPROTEIN phosphatases
ISLANDS of Langerhans
PANCREATIC beta cells
INSULIN synthesis regulation
MAGNESIUM metabolism
ENZYME metabolism
GLUTAMIC acid metabolism
ANIMAL experimentation
CELL culture
COMPARATIVE studies
ESTERASES
GLUCOSE
IMIDAZOLES
RESEARCH methodology
MEDICAL cooperation
NUCLEOSIDES
RATS
RESEARCH
TRANSFERASES
EVALUATION research
PHARMACODYNAMICS
Subjects
Details
- Language :
- English
- ISSN :
- 00121797
- Volume :
- 50
- Issue :
- 7
- Database :
- Complementary Index
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 4760726
- Full Text :
- https://doi.org/10.2337/diabetes.50.7.1580