Regulation of interplay between autophagy and apoptosis in the diabetic heart

Zou, Ming-Hui; Xie, Zhonglin

doi:10.4161/auto.23577

Cited by 93 publications

(77 citation statements)

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“…AMP-activated protein kinase (AMPK) functions as an intracellular energy sensor that maintains energy homeostasis (5) in addition to regulating protein synthesis (46), apoptosis (4), and autophagy (18,52,53,58). Activation of AMPK leads to the phosphorylation of a number of target molecules, resulting in the downregulation of anabolic pathways (to conserve ATP) and the upregulation of catabolic pathways (to generate more ATP) (5).…”

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confidence: 99%

Suppression of the mTORC1/STAT3/Notch1 pathway by activated AMPK prevents hepatic insulin resistance induced by excess amino acids

Zou

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Nutrient overload is associated with the development of obesity, insulin resistance, and type 2 diabetes. However, the underlying mechanisms for developing insulin resistance in the presence of excess nutrients are incompletely understood. We investigated whether activation of AMP-activated protein kinase (AMPK) prevents the hepatic insulin resistance that is induced by the consumption of a high-protein diet (HPD) and the presence of excess amino acids. Exposure of HepG2 cells to excess amino acids reduced AMPK phosphorylation, upregulated Notch1 expression, and impaired the insulin-stimulated phosphorylation of Akt Ser473 and insulin receptor substrate-1 (IRS-1) Tyr612. Inhibition of Notch1 prevented amino acid-induced insulin resistance, which was accompanied by reduced expression of Rbp-Jk, hairy and enhancer of split-1, and forkhead box O1. Mechanistically, mTORC1 signaling was activated by excess amino acids, which then positively regulated Notch1 expression through the activation of the signal transducer and activator of transcription 3 (STAT3). Activation of AMPK by metformin inhibited mTORC1-STAT3 signaling, thereby preventing excess amino acid-impaired insulin signaling. Finally, HPD feeding suppressed AMPK activity, activated mTORC1/STAT3/Notch1 signaling, and induced insulin resistance. Chronic administration of either metformin or rapamycin inhibited the HPD-activated mTORC1/STAT3/Notch1 signaling pathway and prevented hepatic insulin resistance. We conclude that the upregulation of Notch1 expression by hyperactive mTORC1 signaling is an essential event in the development of hepatic insulin resistance in the presence of excess amino acids. Activation of AMPK prevents amino acid-induced insulin resistance through the suppression of the mTORC1/STAT3/Notch1 signaling pathway.

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confidence: 99%

Suppression of the mTORC1/STAT3/Notch1 pathway by activated AMPK prevents hepatic insulin resistance induced by excess amino acids

Zou

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…Previously, FGF21 was reported to increase AMPK Thr-172 phosphorylation in vitro and in vivo , resulting in enhanced mitochondrial oxidative function in adipocytes [65]. AMPK is a energy sensor that maintains energy homeostasis [66] and is involved in survival and autophagy under diabetic condition [67,68]. FGF21 activated AMPK and induced cardiac protection on cardiac function in rodent hearts [69].…”

Section: Discussionmentioning

confidence: 99%

Fibroblast Growth Factor 21 Protects Against High Glucose Induced Cellular Damage and Dysfunction of Endothelial Nitric-Oxide Synthase in Endothelial Cells

Wang

Song

Xiao

et al. 2014

Cell Physiol Biochem

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Aims: Fibroblast growth factor 21 (FGF21) is a powerful endocrine hormone modulating glucose and lipid metabolism and represents a promising drug for type 2 diabetes. The present study was to determine the effect of FGF21 on high glucose-induced damage and dysfunction in endothelial cells. Methods: The protein expression of β-klotho was examined in human umbilical vein endothelial cell (HUVECs) using immunofluorescence and Western blotting. HUVECs were cultured in medium with normal glucose (NG), high glucose (HG) and HG + FGF21 (30 nM). Cell viability, migration, reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase, nitric oxide (NO) production, intracellular cyclic guanosine monophosphate (cGMP) and endothelial nitric oxide synthase (eNOS) phosphorylation at Ser-1177/Ser-633 sites were measured. Results: β-klotho, the anchor protein of FGF21, is expressed in HUVECs. Administration of FGF21 prevented HG-induced impairment of cell viability, migration, oxidant stress, NO production and intracellular cGMP levels in HUVECs. FGF21 also rescued HG-induced decrease of eNOS phosphorylation at Ser-1177 and Ser-633. HG and FGF21 had no effects on eNOS phosphorylation at Ser-617 and Thr-495. Inhibition of AMP-activated protein kinase (AMPK), but not Akt or Ca²⁺/calmodulin-dependent protein kinase II, abolished the protective effect of FGF21 on eNOS phosphorylation at Ser-1177. The protective effect of FGF21 on eNOS phosphorylation at Ser-633 was also abolished by inhibition of AMPK but not by Akt or cAMP-dependent protein kinase A. Conclusion: Our results provide the first evidence that FGF21 protects against high glucose induced cell damage and eNOS dysfunction in an AMPK-dependent manner in HUVECs, and suggest that FGF21 may be a promoting therapeutic agent for vascular complications in diabetes.

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“…In addition, AMPK also regulates many other cellular processes, including mitochondrial biogenesis, 28,29 apoptosis, and autophagy. [30][31][32][33] As autophagy and AMPK are both stimulated by nutrient deprivation, 34,35 it is reasonable to connect AMPK activation to increased autophagic activity. Indeed, activated AMPK phosphorylates and activates ULK1 (unc-51 like autophagy activating kinase 1), a mammalian ortholog of yeast Atg1 (autophagy-related 1), which initiates the autophagic process.…”

Section: Deletion Of Prkaa1 Reduces Ulk1 Phosphorylation In Mouse Tfrcmentioning

confidence: 99%

PRKAA1/AMPKα1 is required for autophagy-dependent mitochondrial clearance during erythrocyte maturation

et al. 2014

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Regulation of interplay between autophagy and apoptosis in the diabetic heart

Cited by 93 publications

References 0 publications

Suppression of the mTORC1/STAT3/Notch1 pathway by activated AMPK prevents hepatic insulin resistance induced by excess amino acids

Suppression of the mTORC1/STAT3/Notch1 pathway by activated AMPK prevents hepatic insulin resistance induced by excess amino acids

Fibroblast Growth Factor 21 Protects Against High Glucose Induced Cellular Damage and Dysfunction of Endothelial Nitric-Oxide Synthase in Endothelial Cells

PRKAA1/AMPKα1 is required for autophagy-dependent mitochondrial clearance during erythrocyte maturation

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