Please use this identifier to cite or link to this item: http://dl.umsu.ac.ir/handle/Hannan/42740
Title: Glucose and palmitate uncouple AMPK from autophagy in human aortic endothelial cells
Authors: José M. Cacicedo;Neil B. Ruderman;Yasuo Ido
subject: endothelium; autophagy; palmitate; glucose; AMPK
Year: 2015
Abstract: Weikel KA, Cacicedo JM, Ruderman NB, Ido Y. Glucose and palmitate uncouple AMPK from autophagy in human aortic endothe- lial cells. Am J Physiol Cell Physiol 308: C249–C263, 2015. First published October 29, 2014; doi:10.1152/ajpcell.00265.2014.—Dys- regulated autophagy and decreased AMP-activated protein kinase (AMPK) activity are each associated with atherogenesis. Atherogen- esis is preceded by high circulating concentrations of glucose and fatty acids, yet the mechanism by which these nutrients regulate autophagy in human aortic endothelial cells (HAECs) is not known. Furthermore, whereas AMPK is recognized as an activator of au- tophagy in cells with few nutrients, its effects on autophagy in nutrient-rich HAECs has not been investigated. We maintained and passaged primary HAECs in media containing 25 mM glucose and incubated them subsequently with 0.4 mM palmitate. These condi- tions impaired basal autophagy and rendered HAECs more suscepti- ble to apoptosis and adhesion of monocytes, outcomes attenuated by the autophagy activator rapamycin. Glucose and palmitate diminished AMPK activity and phosphorylation of the uncoordinated-51-like kinase 1 (ULK1) at Ser555, an autophagy-activating site targeted by AMPK. 5-Aminoimidazole-4-carboxamide-1- - D -ribofuranoside (AICAR)- mediated activation of AMPK phosphorylated acetyl-CoA carboxy- lase, but treatment with AICAR or other AMPK activators (A769662, phenformin) did not restore ULK1 phosphorylation or autophagosome formation. To determine whether palmitate-induced ceramide accu- mulation contributed to this finding, we overexpressed a ceramide- metabolizing enzyme, acid ceramidase. The increase in acid cerami- dase expression ameliorated the effects of excess nutrients on ULK1 phosphorylation, without altering the effects of the AMPK activators. Thus, unlike low nutrient conditions, AMPK becomes uncoupled from autophagy in HAECs in a nutrient-rich environment, such as that found in patients with increased cardiovascular risk. These findings suggest that combinations of AMPK-independent and AMPK-depen- dent therapies may be more effective alternatives than either therapy alone for treating nutrient-induced cellular dysfunction.
URI: http://dl.umsu.ac.ir/handle/Hannan/42740
Appears in Collections:American Journal of Physiology(Cell physiology) 2015

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