PRKAA1/AMPKα1-driven glycolysis in endothelial cells exposed to disturbed flow protects against atherosclerosis

Yang, Qiuhua; Xu, Jiean; Ma, Qian; Liu, Zhiping; Varadarajan, Sudhahar; Cao, Yapeng; Wang, Lina; Zeng, Xiangwu; Zhou, Yuwen; Zhang, Min; Xu, Yiming; Wang, Yong; Weintraub, Neal L.; Zhang, Chunxiang; Fukai, Tohru; Wu, Chaodong; Huang, Lei; Han, Zhen; Wang, Tao; Fulton, David; Hong, Mei; Huo, Yuqing

doi:10.1038/s41467-018-07132-x

Cited by 105 publications

(83 citation statements)

References 61 publications

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“…AMPK, a well-known energy sensor, could switch on glycolysis and induce autophagy to maintain ATP level 45 . It has been reported that AMPK could phosphorylate ULK1 to form PI3K complex, leading to autophagy induction 46,47 .…”

Section: Discussionmentioning

confidence: 99%

MCT1 relieves osimertinib-induced CRC suppression by promoting autophagy through the LKB1/AMPK signaling

et al. 2019

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Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide. Development of novel chemotherapeutics is still required to enable successful treatment and improve survival for CRC patients. Here, we found that osimertinib (OSI) exhibits potent anti-CRC effects by inducing apoptosis, independent of its selective inhibitory activity targeting the EGFR T790M mutation. Intriguingly, OSI treatment triggers autophagic flux in CRC cells. Inhibition of autophagy markedly augments OSI-induced apoptosis and growth inhibition in CRC cells, suggesting a protective role of autophagy in response to OSI treatment. Mechanistically, OSI upregulates the expression of monocarboxylate transporter 1 (MCT1) and subsequently activates LKB1/AMPK signaling, leading to autophagy induction in CRC cells. Notably, OSI significantly exaggerates the sensitivity of CRC cells to the first-line drugs 5-fluorouracil or oxaliplatin. Taken together, our study unravels a novel mechanism of OSI-mediated protective autophagy involving MCT1/LKB1/AMPK signaling, and suggests the use of OSI as a potential agent for clinical CRC treatment.

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Section: Discussionmentioning

confidence: 99%

MCT1 relieves osimertinib-induced CRC suppression by promoting autophagy through the LKB1/AMPK signaling

et al. 2019

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“…The results showed that the mRNA levels of Prkaa1 and Prkaa2 were much higher in leukocytes from adipose tissues of mice fed HFD for 8 weeks than mice fed chow diet (CD) ( Figure 1B ). Prkaa1 is the major isoform of Prkaa in leukocytes ( Zhang et al, 2017 ), and our recent study shows a critical role of Prkaa1 in metabolic regulation in vascular cells ( Yang et al, 2018 ). We analyzed expression of metabolic genes in sorted cells with qPCR.…”

Section: Resultsmentioning

confidence: 99%

“…AMPK/PRKA also has been reported to regulate glycolytic flux through the pathway by phosphorylating phosphofructo-2-kinase/fructose 2,6-bisphosphatase 3 (PFKFB3), which affects the activity of PFK1, a rate-limiting enzyme in glycolysis ( Bando et al, 2005 ). Our previous study has demonstrated that AMPK/PRKA regulates glycolysis in part via the HIF1α pathway ( Yang et al, 2018 ), and increased HIF1A expression promotes glycolysis, resulting in a rapid supply of ATP ( Semenza, 2012 ). In addition to stimulating glycolysis, AMPK/PRKA also increases FAO by a reduction of the activity of ACC, decreased the level of malonyl-CoA, and resulted in increased fatty acid import into mitochondria for β-oxidation ( Saggerson, 2008 ).…”

Section: Discussionmentioning

confidence: 99%

“…AMPKa1/PRKAA1 is a well-characterized molecule for modulating cellular metabolism, including metabolism of glucose and fatty acid oxidation, in metabolic tissue/organs ( Garcia and Shaw, 2017 ; Boudaba et al, 2018 ; Wu et al, 2018 ). For cardiovascular cells, we recently examined the role of AMPKa1/PRKAA1/Prkaa1 in glucose metabolism of cultured human endothelial cells and mouse endothelial cells in vivo ( Yang et al, 2018 ); the role of AMPKa1/PRKAA1/Prkaa1 in macrophage metabolism, such as glucose metabolism, has not been studied. Here, we examined glycolysis in Prkaa1 -deficient myeloid cells and the effects of this changed metabolism to myeloid cell recruitment and survival, as well as to the development of chronic inflammatory diseases, including diet-induced diabetes and atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

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Prkaa1 Metabolically Regulates Monocyte/Macrophage Recruitment and Viability in Diet-Induced Murine Metabolic Disorders

Yang

et al. 2021

Front. Cell Dev. Biol.

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Myeloid cells, including monocytes/macrophages, primarily rely on glucose and lipid metabolism to provide the energy and metabolites needed for their functions and survival. AMP-activated protein kinase (AMPK, its gene is PRKA for human, Prka for rodent) is a key metabolic sensor that regulates many metabolic pathways. We studied recruitment and viability of Prkaa1-deficient myeloid cells in mice and the phenotype of these mice in the context of cardio-metabolic diseases. We found that the deficiency of Prkaa1 in myeloid cells downregulated genes for glucose and lipid metabolism, compromised glucose and lipid metabolism of macrophages, and suppressed their recruitment to adipose, liver and arterial vessel walls. The viability of macrophages in the above tissues/organs was also decreased. These cellular alterations resulted in decreases in body weight, insulin resistance, and lipid accumulation in liver of mice fed with a high fat diet, and reduced the size of atherosclerotic lesions of mice fed with a Western diet. Our results indicate that AMPKα1/PRKAA1-regulated metabolism supports monocyte recruitment and macrophage viability, contributing to the development of diet-induced metabolic disorders including diabetes and atherosclerosis.

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“…AMPK is a vital regulator of energy metabolism. In the prevention and treatment of AS, AMPK plays an important role in promoting cholesterol efflux, accelerating fatty acid oxidation and inhibiting inflammation [ 32 – 34 ]. Our results showed that colchicine treatment significantly increased the expression of phosphorylated AMPK and the downstream protein SIRT1.…”

Section: Discussionmentioning

confidence: 99%

Colchicine Alleviates Cholesterol Crystal-Induced Endothelial Cell Pyroptosis through Activating AMPK/SIRT1 Pathway

Yang

Liu

et al. 2020

Oxidative Medicine and Cellular Longevity

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Cholesterol crystal- (CC-) induced endothelial cell inflammation and pyroptosis play an important role in the development of cardiovascular diseases, especially in atherosclerosis (AS). Increasing evidence suggests that cholesterol crystals are known to be a pivotal pathological marker of atherosclerotic plaque vulnerability. As a classical nonspecific anti-inflammatory drug, colchicine has been widely used in the treatment of acute gout. However, whether colchicine could alleviate CC-induced endothelial cell injury and the related mechanisms remains to be addressed. In this study, the protective effect of colchicine on human umbilical vein endothelial cells (HUVECs) was confirmed. Our results revealed that after cotreatment with colchicine and cholesterol crystals in endothelial cells, the uptake of cholesterol crystals was significantly decreased, the cell viability was obviously increased, and the release of lactate dehydrogenase (LDH) and the number of pyroptotic cells decreased significantly; then, the expression of NLRP3 inflammasome-related proteins and various inflammatory factors was also visibly suppressed; moreover, as a potent activator of NLRP3 inflammasome, the intracellular ROS level was clearly reduced, while mitochondrial membrane potential improved significantly. In addition, the expression levels of AMP-dependent kinase (AMPK) pathway-related proteins as well as various antioxidant enzymes were elevated notably in varying degrees. However, the above effects of colchicine were completely offset by the treatment of siRNA targeting AMPKα and Sirtuin1 (SIRT1). Therefore, we conclude that colchicine plays a crucial role in alleviating the intracellular inflammatory response and NLRP3 inflammation activation, attenuating the levels of cellular oxidative stress and pyroptosis in endothelial cells via regulating AMPK/SIRT1 signaling, which may be a concrete mechanism for the secondary prevention of cardiovascular diseases.

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PRKAA1/AMPKα1-driven glycolysis in endothelial cells exposed to disturbed flow protects against atherosclerosis

Cited by 105 publications

References 61 publications

MCT1 relieves osimertinib-induced CRC suppression by promoting autophagy through the LKB1/AMPK signaling

MCT1 relieves osimertinib-induced CRC suppression by promoting autophagy through the LKB1/AMPK signaling

Prkaa1 Metabolically Regulates Monocyte/Macrophage Recruitment and Viability in Diet-Induced Murine Metabolic Disorders

Colchicine Alleviates Cholesterol Crystal-Induced Endothelial Cell Pyroptosis through Activating AMPK/SIRT1 Pathway

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