Sestrin2 as a Potential Target for Regulating Metabolic-Related Diseases

Gong, Linan; Wang, Zanzan; Wang, Zhenggui; Zhang, Zhiguo

doi:10.3389/fendo.2021.751020

Cited by 28 publications

(26 citation statements)

References 113 publications

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“…However, AMPK and OS are closely linked in DCM. Sestrin 2, a highly conserved protein that is upregulated under various stress conditions and especially under diabetes-related OS, has been shown to activate AMPK and inhibit mTOR, thereby ameliorating IR ( 75 ).…”

Section: Oxidative Stress- Related Pathwaysmentioning

confidence: 99%

Signaling Pathways Related to Oxidative Stress in Diabetic Cardiomyopathy

Peng

et al. 2022

Front. Endocrinol.

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Diabetes is a chronic metabolic disease that is increasing in prevalence and causes many complications. Diabetic cardiomyopathy (DCM) is a complication of diabetes that is associated with high mortality, but it is not well defined. Nevertheless, it is generally accepted that DCM refers to a clinical disease that occurs in patients with diabetes and involves ventricular dysfunction, in the absence of other cardiovascular diseases, such as coronary atherosclerotic heart disease, hypertension, or valvular heart disease. However, it is currently uncertain whether the pathogenesis of DCM is directly attributable to metabolic dysfunction or secondary to diabetic microangiopathy. Oxidative stress (OS) is considered to be a key component of its pathogenesis. The production of reactive oxygen species (ROS) in cardiomyocytes is a vicious circle, resulting in further production of ROS, mitochondrial DNA damage, lipid peroxidation, and the post-translational modification of proteins, as well as inflammation, cardiac hypertrophy and fibrosis, ultimately leading to cell death and cardiac dysfunction. ROS have been shown to affect various signaling pathways involved in the development of DCM. For instance, OS causes metabolic disorders by affecting the regulation of PPARα, AMPK/mTOR, and SIRT3/FOXO3a. Furthermore, OS participates in inflammation mediated by the NF-κB pathway, NLRP3 inflammasome, and the TLR4 pathway. OS also promotes TGF-β-, Rho-ROCK-, and Notch-mediated cardiac remodeling, and is involved in the regulation of calcium homeostasis, which impairs ATP production and causes ROS overproduction. In this review, we summarize the signaling pathways that link OS to DCM, with the intention of identifying appropriate targets and new antioxidant therapies for DCM.

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Section: Oxidative Stress- Related Pathwaysmentioning

confidence: 99%

Signaling Pathways Related to Oxidative Stress in Diabetic Cardiomyopathy

Peng

et al. 2022

Front. Endocrinol.

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“…This enzyme maintains mitochondrial homeostasis and is activated when the ratio of AMP or ADP to ATP increases, and compensates for energy loss by upregulating glycolysis ( 80 ). Tumors such as breast ( 81 ), pancreatic ( 82 ) and prostate cancer ( 83 ) are related to obesity, which in turn is associated with the AMPK/mTOR metabolic pathway ( 84 ). AMPK is the cell's ‘energy receptor’ being activated when energy is lacking and inhibited when energy is excessive.…”

Section: Metformin As An Antitumor Candidate Drugmentioning

confidence: 99%

“…AMPK is the cell's ‘energy receptor’ being activated when energy is lacking and inhibited when energy is excessive. After AMPK is activated, it can regulate multiple pathways, including the mTOR pathway, thus dominating intracellular protein synthesis ( 84 ). Most studies have shown that metformin inhibits obesity-related tumors through the AMPK/mTOR pathway ( 85 , 86 ).…”

Section: Metformin As An Antitumor Candidate Drugmentioning

confidence: 99%

Metformin: A promising drug for human cancers (Review)

Huang

Zhao

et al. 2022

Oncol Lett

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Small-molecule chemical drugs are of great significance for tumor-targeted and individualized therapies. However, the development of new small-molecule drugs, from basic experimental research and clinical trials to final application in clinical practice, is a long process that has a high cost. It takes at least 5 years for most drugs to be developed in the laboratory to prove their effectiveness and safety. Compared with the development of new drugs, repurposing traditional non-tumor drugs can be a shortcut. Metformin is a good model for a new use of an old drug. In recent years, the antitumor efficacy of metformin has attracted much attention. Epidemiological data and in vivo , and in vitro experiments have shown that metformin can reduce the incidence of cancer in patients with diabetes and has a strong antagonistic effect on metabolism-related tumors. Recent studies have shown that metformin can induce autophagy in esophageal cancer cells, mainly by inhibiting inflammatory signaling pathways. In recent years, studies have shown that the antitumor functions and mechanisms of metformin are multifaceted. The present study aims to review the application of metformin in tumor prevention and treatment.

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“…Sestrin2 (Sesn2) is a highly conserved stress-inducible protein expressed in multiple tissues (e.g., liver, muscles, heart, and kidneys); it acts as a critical regulator of obesity-associated pathologies ( Gong et al, 2021 ). As a stress-inducible metabolic protein, Sesn2 participates in the maintenance of metabolic homeostasis by regulating responses to various stresses, including oxidative stress and metabolic pathologies ( Sun W. et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Empagliflozin activates Sestrin2-mediated AMPK/mTOR pathway and ameliorates lipid accumulation in obesity-related nonalcoholic fatty liver disease

Zhang²,

Kuang³

et al. 2022

Front. Pharmacol.

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Empagliflozin (EMPA) therapy has led to improvements in patients with non-alcoholic fatty liver disease (NAFLD). Sestrin2 is a stress-inducible protein that controls the AMPK-mTOR pathway and inhibits oxidative damage in cells. This study investigated the functional implications of EMPA on the multifactorial pathogenesis of NAFLD and potential underlying molecular mechanisms of pathogenesis. An in vitro model of NAFLD was established by treating HepG2 cells with palmitic acid (PA); an in vivo model of NAFLD was generated by feeding C57BL/6 mice a high-fat diet. Investigations of morphology and lipid deposition in liver tissue were performed. Expression patterns of Sestrin2 and genes related to lipogenesis and inflammation were assessed by reverse transcription polymerase chain reaction. Protein levels of Sestrin2 and AMPK/mTOR pathway components were detected by Western blotting. NAFLD liver tissues and PA-stimulated HepG2 cells exhibited excessive lipid production and triglyceride secretion, along with upregulation of Sestrin2 and increased expression of lipogenesis-related genes. EMPA treatment reversed liver damage by upregulating Sestrin2 and activating the AMPK-mTOR pathway. Knockdown of Sestrin2 effectively increased lipogenesis and enhanced the mRNA expression levels of lipogenic and pro-inflammatory genes in PA-stimulated HepG2 cells; EMPA treatment did not affect these changes. Furthermore, Sestrin2 knockdown inhibited AMPK-mTOR signaling pathway activity. The upregulation of Sestrin2 after treatment with EMPA protects against lipid deposition-related metabolic disorders; it also inhibits lipogenesis and inflammation through activation of the AMPK-mTOR signaling pathway. These results suggest that Sestrin2 can be targeted by EMPA therapy to alleviate lipogenesis and inflammation in obesity-related NAFLD.

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Sestrin2 as a Potential Target for Regulating Metabolic-Related Diseases

Cited by 28 publications

References 113 publications

Signaling Pathways Related to Oxidative Stress in Diabetic Cardiomyopathy

Signaling Pathways Related to Oxidative Stress in Diabetic Cardiomyopathy

Metformin: A promising drug for human cancers (Review)

Empagliflozin activates Sestrin2-mediated AMPK/mTOR pathway and ameliorates lipid accumulation in obesity-related nonalcoholic fatty liver disease

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