Negative regulation of AMPK signaling by high glucose via E3 ubiquitin ligase MG53

Jiang, Peng; Ren, Lejiao; Li, Zhi; Yu, Zhong Ying; Lv, Fengxiang; Xu, Fengli; Peng, Wei; Bai, Xiaoyu; Cheng, Kunlun; Li, Quan; Zhang, Xiuqin; Wang, Xianhua; Zhang, Yan; Yang, Dian; Hu, Xinli; Xiao, Rui‐Ping

doi:10.1016/j.molcel.2020.12.008

Cited by 74 publications

(70 citation statements)

References 40 publications

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“…Intracellular protein degradation mainly includes the ubiquitin pathway, autophagy pathway and caspase pathway, amongst which autophagy dysfunction is considered an important pathogenic mechanism of diabetes 30,31 . Recent research proved that the increase of ROS in high glucose suppressed the binding between LKB1 and AMPKα, which reduces p‐AMPKα T172 levels, resulting in AMPK inactivation 32 . It is well known that AMPK, a key enzyme in maintaining metabolic homeostasis, is closely related to the decline of autophagy in diabetes 33 .…”

Section: Discussionmentioning

confidence: 99%

Kakonein restores diabetes‐induced endothelial junction dysfunction via promoting autophagy‐mediated NLRP3 inflammasome degradation

Lian

Liu

Han

et al. 2021

J Cellular Molecular Medi

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In diabetes‐induced complications, inflammatory‐mediated endothelial dysfunction is the core of disease progression. Evidence shows that kakonein, an isoflavone common in Pueraria, can effectively treat diabetes and its complications. Therefore, we explored whether kakonein protects cardiovascular endothelial function by inhibiting inflammatory responses. In this study, C57BL/6J mice were injected with streptozocin to establish a diabetes model and treated with kakonein or metformin for 7 days. The protective effect of kakonein on cardiovascular endothelial junctions and NLRP3 inflammasome activation was verified through immunofluorescence and ELISA assay. In addition, the regulation of autophagy on the NLRP3 inflammasome was investigated through Western blot, immunofluorescence and RT‐qPCR. Results showed that kakonein restored the function of endothelial junctions and inhibited the assembly and activation of the NLRP3 inflammasome. Interestingly, kakonein decreased the expression of NLRP3 inflammasome protein by not reducing the transcriptional levels of NLRP3 and caspase‐1. Kakonein activated autophagy in an AMPK‐dependent manner, which reduced the activation of the NLRP3 inflammasome. In addition, kakonein inhibited both hyperglycaemia‐induced cardiovascular endothelial junction dysfunction and NLRP3 inflammasome activation, similar to autophagy agonist. Our findings indicated that kakonein exerts a protective effect on hyperglycaemia‐induced chronic vascular disease by regulating the NLRP3 inflammasome through autophagy.

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Section: Discussionmentioning

confidence: 99%

Kakonein restores diabetes‐induced endothelial junction dysfunction via promoting autophagy‐mediated NLRP3 inflammasome degradation

Lian

Liu

Han

et al. 2021

J Cellular Molecular Medi

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“…In the human study, the elevation is observed in the liver along with insulin resistance in a study of acute overfeeding [9]. Elevation in the ATP/ADP and ATP/AMP ratios provides a perfect mechanism for the fallen AMPK activity in obese rodents and patients [1,[16][17][18]. In addition, the ATP concept is supported by the broad indirect evidence in clinical and laboratory studies.…”

Section: Atp As a Signal Of Energy Surplus For Insulin Resistancementioning

confidence: 96%

“…Elevation induces ATP/ADP and ATP/AMP ratios, which provide a perfect mechanism for the reduced AMPK activity in the liver/muscle of obese rodents and patients [1,15]. The AMPK activity is decreased in the conditions of insulin resistance with reduction in the AMPK phosphorylation status (T172) and AMPK proteins [16][17][18]. The protein reduction is investigated in the cellular models of glucose stimulation, and the mechanism is ubiquitin-mediated protein degradation after glucoseinduced ROS [18].…”

Section: Atp As a Signal Of Energy Surplus For Insulin Resistancementioning

confidence: 99%

“…The AMPK activity is decreased in the conditions of insulin resistance with reduction in the AMPK phosphorylation status (T172) and AMPK proteins [16][17][18]. The protein reduction is investigated in the cellular models of glucose stimulation, and the mechanism is ubiquitin-mediated protein degradation after glucoseinduced ROS [18]. Mitochondrial overloading by the energy substrates, such as glucose, fatty acid, and amino acid, is a primary cause of insulin resistance in the skeletal muscle through mitochondrial dysfunction, mitochondrial inflexibility, and activation of the mTOR/S6K pathway [3,19,20].…”

Section: Atp As a Signal Of Energy Surplus For Insulin Resistancementioning

confidence: 99%

“…(2) reduction in ATP production by targeting the respiration chain of mitochondria with medicines, including metformin [36], berberine [37,38], mitochondrial uncouplers [39][40][41], and gene mutation [32,33]; and (3) depletion of ATP by physical exercise. The literature strongly supports the ATP concept although some studies suggest that ATP is not elevated by the substrate oversupply [18]. However, the proof of concept needs a real-time test of intracellular or intramitochondrial ATP levels in vivo.…”

Section: Atp As a Signal Of Energy Surplus For Insulin Resistancementioning

confidence: 99%

See 2 more Smart Citations

Mechanism of insulin resistance in obesity: a role of ATP

2021

Front. Med.

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Obesity increases the risk of type 2 diabetes through the induction of insulin resistance. The mechanism of insulin resistance has been extensively investigated for more than 60 years, but the essential pathogenic signal remains missing. Existing hypotheses include inflammation, mitochondrial dysfunction, hyperinsulinemia, hyperglucagonemia, glucotoxicity, and lipotoxicity. Drug discoveries based on these hypotheses are unsuccessful in the development of new medicines. In this review, multidisciplinary literature is integrated to evaluate ATP as a primary signal for insulin resistance. The ATP production is elevated in insulin-sensitive cells under obese conditions independent of energy demand, which we have named “mitochondrial overheating.” Overheating occurs because of substrate oversupply to mitochondria, leading to extra ATP production. The ATP overproduction contributes to the systemic insulin resistance through several mechanisms, such as inhibition of AMPK, induction of mTOR, hyperinsulinemia, hyperglucagonemia, and mitochondrial dysfunction. Insulin resistance represents a feedback regulation of energy oversupply in cells to control mitochondrial overloading by substrates. Insulin resistance cuts down the substrate uptake to attenuate mitochondrial overloading. The downregulation of the mitochondrial overloading by medicines, bypass surgeries, calorie restriction, and physical exercise leads to insulin sensitization in patients. Therefore, ATP may represent the primary signal of insulin resistance in the cellular protective response to the substrate oversupply. The prevention of ATP overproduction represents a key strategy for insulin sensitization.

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Biochemotaxis‐Oriented Engineering Bacteria Expressing GLP‐1 Enhance Diabetes Therapy by Regulating the Balance of Immune

Wang,

Shi,

Peng

et al. 2024

Adv Healthcare Materials

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Glucagon like peptide‐1 (GLP‐1) is an effective hypoglycemic drug that can repair the pancreas β Cells and promote insulin secretion. However, GLP‐1 has poor stability and lack of target ability, which makes it difficult to reach the site of action to exert its efficacy. Here, we introduce GLP‐1‐expressing plasmids into the Escherichia coli Nissle 1917 (EcN) and form a lipid membrane through simple self‐assembly on its surface, resulting in an oral delivery system (LEG) capable of resisting the harsh environment of the gastrointestinal tract. The system utilizes the chemotactic properties of probiotics to achieve efficient enrichment at the pancreatic site, and protects islet β cells from destruction by regulating the balance of immune cells. More interestingly, LEG not only continuously produces GLP‐1 to restore pancreatic islet β cell function and secrete insulin to control blood sugar levels, but also regulates the intestinal flora and increases the richness and diversity of probiotics. In mice diabetes models, oral administration of LEG only once every other day had good biosafety and compliance, and achieved long‐term control of blood glucose. Therefore, this strategy not only provides an oral delivery platform for pancreatic targeting, but also opens up new avenues for reversing diabetes.This article is protected by copyright. All rights reserved

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Negative regulation of AMPK signaling by high glucose via E3 ubiquitin ligase MG53

Cited by 74 publications

References 40 publications

Kakonein restores diabetes‐induced endothelial junction dysfunction via promoting autophagy‐mediated NLRP3 inflammasome degradation

Kakonein restores diabetes‐induced endothelial junction dysfunction via promoting autophagy‐mediated NLRP3 inflammasome degradation

Mechanism of insulin resistance in obesity: a role of ATP

Biochemotaxis‐Oriented Engineering Bacteria Expressing GLP‐1 Enhance Diabetes Therapy by Regulating the Balance of Immune

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