title: Modulation of hepatic copper-ATPase activity by insulin and glucagon involves protein kinase A (PKA) signaling pathway.
abstract: Different studies have revealed copper imbalance in individuals suffering from diabetes and obesity, suggesting that regulation of glucose and/or fat metabolism could modulate cellular copper homeostasis. To test this hypothesis we investigated whether the key hormones of energy metabolism, insulin and glucagon, regulate the functional properties of the major hepatic copper-transporter, ATP7B (i.e., copper-dependent ATPase activity). We demonstrated that insulin reverses the effect of copper and stimulates retrograde trafficking of ATP7B from the canalicular membranes, consistent with the enhanced ability of ATP7B to sequester copper away from the cytosol. Physiological concentrations of insulin increase endogenous ATP7B activity in cultured hepatic cells and in tissues by 40%, whereas glucagon inhibits this activity by 70%. These effects were cancelled out when insulin and glucagon were combined. We also demonstrated that the opposite effects of the hormones on ATP7B activity involve receptor-mediated signaling pathways and membrane-bound kinases (PKA and PKB/Akt), which are reciprocally regulated by insulin and glucagon. Inhibiting insulin signaling at the level of its Tyr-kinase receptor, PI3K or PKB/Akt restored the basal activity of ATP7B. Insulin reduced endogenous PKA activity, whereas glucagon promoted PKA stimulation by approximately 100%. These findings demonstrate that the physiological modulation of ATP7B activity is linked to energy metabolism via insulin and glucagon, and could help to understand the mechanisms involved in the disruption of copper homeostasis in diabetic and obese patients.
authors: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil; CAPES Foundation, Ministry of Education of Brazil, 70040-020 Brasília, DF, Brazil.
authors: Elaine
authors: E
authors: Hilário-Souza
authors: CEA, BIG-LCBM, F-38000 Grenoble, France; CNRS, BIG-LCBM, F-38000 Grenoble, France; Université Grenoble Alpes, BIG-LCBM, F-38000 Grenoble, France.
authors: Martine
authors: M
authors: Cuillel
authors: CEA, BIG-LCBM, F-38000 Grenoble, France; CNRS, BIG-LCBM, F-38000 Grenoble, France; Université Grenoble Alpes, BIG-LCBM, F-38000 Grenoble, France.
authors: Elisabeth
authors: E
authors: Mintz
authors: CEA, BIG-LCBM, F-38000 Grenoble, France; CNRS, BIG-LCBM, F-38000 Grenoble, France; Université Grenoble Alpes, BIG-LCBM, F-38000 Grenoble, France.
authors: Peggy
authors: P
authors: Charbonnier
authors: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil; National Center of Structural Biology and Bioimaging - CENABIO, 21941 Rio de Janeiro, Brazil.
authors: Adalberto
authors: A
authors: Vieyra
authors: Université Paris-Sud, UMR-S 757, F-91405 Orsay, France; INSERM, UMR-S 757, F-91405 Orsay, France.
authors: Doris
authors: D
authors: Cassio
authors: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil; National Center of Structural Biology and Bioimaging - CENABIO, 21941 Rio de Janeiro, Brazil. Electronic address: lowe@biof.ufrj.br.
authors: Jennifer
authors: J
authors: Lowe
keywords: Copper imbalance; Copper transport; Glucagon; Insulin; Protein kinase A (PKA)