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Dexfenfluramine modulates hepatic glycogen metabolism by a calcium-dependent pathway

Abstract : In this study, the mechanism of action of dexfenfluramine (DEXF) at the hepatic level was investigated. The drug is shown to bind to the alpha(1)-adrenergic receptor and to increase intracellular calcium in isolated rat hepatocytes, thereby activating phosphorylase via a calcium-dependent mechanism. Moreover, phosphorylase activation by DEXF was inhibited by different agents that interfere with the alpha(1)-adrenergic signalling system: prazosin, phorbol 12 alpha-myristate 13 beta-acetate (PMA), and DEXF itself. We also show that phosphorylase activation induced by catecholamines and analogues (epinephrine, phenylephrine), whose actions are mediated by a calcium-dependent mechanism, was counteracted by the drug in the submillimolar range (0.1-1 mM). The activation of glycogenolysis by the drug is accompanied by a stimulation of the glycolytic flux (54% increase in lactate plus pyruvate accumulation), consistent with an increase in fructose-2,6-bisphosphate (F-2,6-BP) levels (36%). These results indicate that the interaction of DEXF with the alpha(1)-adrenergic receptor channels glucose 6-phosphate derived from glycogen away from glucose production into the glycolytic pathway.
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https://hal.inrae.fr/hal-03324856
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Submitted on : Tuesday, August 24, 2021 - 9:52:33 AM
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Blandine Comte, A. Romanelli, P. Haddad, G. van de Werve. Dexfenfluramine modulates hepatic glycogen metabolism by a calcium-dependent pathway. Canadian Journal of Physiology and Pharmacology, NRC Research Press, 1997, 75 (7), pp.842-848. ⟨10.1139/cjpp-75-7-842⟩. ⟨hal-03324856⟩

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