Activation of Acetyl-Coa Carboxylase by a Glutamate-and Magnesium-Sensitive Protein Phosphatase in the Islet β-Cell

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Abstract

Acetyl-CoA carboxylase (ACC) catalyzes the formation of malonyl-CoA, a precursor in the biosynthesis of longchain 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 β-cell. ACC was quantitated in normal rat islets, human islets, and clonal β-cells (HIT-15 or INS-1) using a [14C]bicarbonate fixation assay. In the β-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 PP2 A-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 β-cells. Together, our data provide evidence for a unique regulatory mechanism for the activation of ACC in the pancreatic β-cell, leading to the generation of physiological signals that may be relevant for physiological insulin secretion.

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Kowluru, A., Chen, H. Q., Modrick, L. M., & Stefanelli, C. (2001). Activation of Acetyl-Coa Carboxylase by a Glutamate-and Magnesium-Sensitive Protein Phosphatase in the Islet β-Cell. Diabetes, 50(7), 1580–1587. https://doi.org/10.2337/diabetes.50.7.1580

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