Estrogen receptor alpha inactivation

CHEBI:35366

CHEBI fatty acid

CHEBI:26523

CHEBI reactive oxygen species

GO:0006635

GO fatty acid beta-oxidation

GO:1903409

GO reactive oxygen species biosynthetic process

MP:0003674

MP oxidative stress

WIKI decreased

WIKI increased

9606

NCBI Homo sapiens

WikiUser_28

Vertebrates

Estrogen receptor alpha inactivation

ERa inactivation

Molecular

AOPWiki 2023-04-05T05:36:56

2023-04-10T13:29:15

Decreased, Mitochondrial fatty acid beta-oxidation

Molecular

Fatty acid oxidation in liver tissue is controlled by PPARalpha signaling networks (Evans et al 2004). The PPARalpha signaling network controls expression of the genes within metabolic pathways that catalyze fatty acid oxidation reactions (Desvergne and Wahli 1999).

A variety of approaches establishing the effects of PPARalpha signaling on fatty acid oxidation are reviewed in Evans et al (2004).

See review for Human PPARalpha signaling in (Evans et al 2004).

CL:0000182

CL hepatocyte

High

Desvergne B, Wahli W (1999) Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocrine Reviews 20(5): 649-688. Evans RM, Barish GD, Wang YX: PPARs and the complex journey to obesity. Nat Med 2004, 10(4):355-361. AOPWiki 2016-11-29T18:41:23

2017-09-16T10:14:56

Increased, Reactive oxygen species

Cellular

Biological State: increased reactive oxygen species (ROS) Biological compartment: an entire cell -- may be cytosolic, may also enter organelles. Reactive oxygen species (ROS) are O2- derived molecules that can be both free radicals (e.g. superoxide, hydroxyl, peroxyl, alcoxyl) and non-radicals (hypochlorous acid, ozone and singlet oxygen) (Bedard and Krause 2007; Ozcan and Ogun 2015). ROS production occurs naturally in all kinds of tissues inside various cellular compartments, such as mitochondria and peroxisomes (Drew and Leeuwenburgh 2002; Ozcan and Ogun 2015). Furthermore, these molecules have an important function in the regulation of several biological processes – they might act as antimicrobial agents or triggers of animal gamete activation and capacitation (Goud et al. 2008; Parrish 2010; Bisht et al. 2017).  However, in environmental stress situations (exposure to radiation, chemicals, high temperatures) these molecules have its levels drastically increased, and overly interact with macromolecules, namely nucleic acids, proteins, carbohydrates and lipids, causing cell and tissue damage (Brieger et al. 2012; Ozcan and Ogun 2015).

Photocolorimetric assays (Sharma et al. 2017; Griendling et al. 2016) or through commercial kits purchased from specialized companies. Yuan, Yan, et al., (2013) described ROS monitoring by using H2-DCF-DA, a redox-sensitive fluorescent dye. Briefly, the harvested cells were incubated with H2-DCF-DA (50 µmol/L final concentration) for 30 min in the dark at 37°C. After treatment, cells were immediately washed twice, re-suspended in PBS, and analyzed on a BD-FACS Aria flow cytometry. ROS generation was based on fluorescent intensity which was recorded by excitation at 504 nm and emission at 529 nm. Lipid peroxidation (LPO) can be measured as an indicator of oxidative stress damage Yen, Cheng Chien, et al., (2013). Chattopadhyay, Sukumar, et al. (2002) assayed the generation of free radicals within the cells and their extracellular release in the medium by addition of yellow NBT salt solution (Park et al., 1968). Extracellular release of ROS converted NBT to a purple colored formazan. The cells were incubated with 100 ml of 1 mg/ml NBT solution for 1 h at 37 °C and the product formed was assayed at 550 nm in an Anthos 2001 plate reader. The observations of the ‘cell-free system’ were confirmed by cytological examination of parallel set of explants stained with chromogenic reactions for NO and ROS.

ROS is a normal constituent found in all organisms.

High Unspecific

High

All life stages

High

B.H. Park, S.M. Fikrig, E.M. Smithwick Infection and nitroblue tetrazolium reduction by neutrophils: a diagnostic aid Lancet, 2 (1968), pp. 532-534 Bedard, Karen, and Karl-Heinz Krause. 2007. “The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology.” Physiological Reviews 87 (1): 245–313. Bisht, Shilpa, Muneeb Faiq, Madhuri Tolahunase, and Rima Dada. 2017. “Oxidative Stress and Male Infertility.” Nature Reviews. Urology 14 (8): 470–85. Brieger, K., S. Schiavone, F. J. Miller Jr, and K-H Krause. 2012. “Reactive Oxygen Species: From Health to Disease.” Swiss Medical Weekly 142 (August): w13659. Chattopadhyay, Sukumar, et al. "Apoptosis and necrosis in developing brain cells due to arsenic toxicity and protection with antioxidants." Toxicology letters 136.1 (2002): 65-76. Drew, Barry, and Christiaan Leeuwenburgh. 2002. “Aging and the Role of Reactive Nitrogen Species.” Annals of the New York Academy of Sciences 959 (April): 66–81. Goud, Anuradha P., Pravin T. Goud, Michael P. Diamond, Bernard Gonik, and Husam M. Abu-Soud. 2008. “Reactive Oxygen Species and Oocyte Aging: Role of Superoxide, Hydrogen Peroxide, and Hypochlorous Acid.” Free Radical Biology & Medicine 44 (7): 1295–1304. Griendling, Kathy K., Rhian M. Touyz, Jay L. Zweier, Sergey Dikalov, William Chilian, Yeong-Renn Chen, David G. Harrison, Aruni Bhatnagar, and American Heart Association Council on Basic Cardiovascular Sciences. 2016. “Measurement of Reactive Oxygen Species, Reactive Nitrogen Species, and Redox-Dependent Signaling in the Cardiovascular System: A Scientific Statement From the American Heart Association.” Circulation Research 119 (5): e39–75. Ozcan, Ayla, and Metin Ogun. 2015. “Biochemistry of Reactive Oxygen and Nitrogen Species.” In Basic Principles and Clinical Significance of Oxidative Stress, edited by Sivakumar Joghi Thatha Gowder. Rijeka: IntechOpen. Parrish, A. R. 2010. “2.27 - Hypoxia/Ischemia Signaling.” In Comprehensive Toxicology (Second Edition), edited by Charlene A. McQueen, 529–42. Oxford: Elsevier. Sharma, Gunjan, Nishant Kumar Rana, Priya Singh, Pradeep Dubey, Daya Shankar Pandey, and Biplob Koch. 2017. “p53 Dependent Apoptosis and Cell Cycle Delay Induced by Heteroleptic Complexes in Human Cervical Cancer Cells.” Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie 88 (April): 218–31. Yen, Cheng Chien, et al. "Inorganic arsenic causes cell apoptosis in mouse cerebrum through an oxidative stress-regulated signaling pathway." Archives of toxicology 85 (2011): 565-575. Yuan, Yan, et al. "Cadmium-induced apoptosis in primary rat cerebral cortical neurons culture is mediated by a calcium signaling pathway." PloS one 8.5 (2013): e64330. AOPWiki 2016-11-29T18:41:29

2023-07-26T14:34:09

Mitochondrial dysfunction

Cellular

AOPWiki 2020-11-02T07:11:18

2020-11-02T07:11:18

Increased, Oxidative Stress

Molecular

CL:0000255

CL eukaryotic cell

AOPWiki 2016-11-29T18:41:29

2022-02-03T14:20:13

Impaired insulin signaling

Cellular

AOPWiki 2023-05-25T09:46:54

2023-05-25T09:46:54

Insulin resistance

Cellular

AOPWiki 2022-06-27T23:17:28

2022-06-27T23:17:28

Metabolic syndrome

Population

AOPWiki 2023-05-25T09:51:12

2023-05-25T09:51:12

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2023-05-25T10:03:48

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2023-05-25T10:04:23

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<table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>MF Specification</th> <th>Effect(s) on the KER</th> <th>Reference(s)</th> </tr> </thead> <tbody> <tr> <td> </td> <td> </td> <td> </td> <td> </td> </tr> </tbody> </table>

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2023-07-31T15:55:25

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b43024dd788> AOPWiki 2023-05-25T10:05:28

2023-05-25T10:05:28

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b43025230f8> AOPWiki 2023-05-25T10:05:48

2023-05-25T10:05:48

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b4302450950> AOPWiki 2023-05-25T10:06:10

2023-05-25T10:06:10

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b43024823b0> AOPWiki 2023-05-25T10:06:37

2023-05-25T10:06:37

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b43024b3938> AOPWiki 2023-05-26T03:22:55

2023-05-26T03:22:55

ERa inactivation alters mitochondrial functions and insulin signalling in skeletal muscle and leads to insulin resistance and metabolic syndrome

ERa inactivation leads to insulin resistance in skeletal muscle and metabolic syndrome

Agnes Aggy

Min Ji Kim Jean-Pascal De Bandt Antoine Girardon Etienne Blanc Xavier Coumoul Karine Audouze

2.5

Estrogens are not only important in the development and functions of the reproductive system, but also play a role in metabolic functions and insulin sensitivity. Thus, before menopause,  women display higher insulin sensitivity and lower propensity to develop metabolic dysfunction-related diseases such as insulin resistance, type 2 diabetes, cancers and cardiovascular diseases than men but, after menopause, incidence of these diseases is similar in both sex [1]. In parallel, hormone replacement therapy has positive effects on insulin resistance [2]. Similarly, men with a mutation in the aromatase gene, who don’t have circulating estrogen, develop insulin resistance that can be reversed by estrogen therapy [3].   Skeletal muscle is known to play a central role in the development of insulin resistance (IR). Due to the important mass of skeletal muscle (30 to 40% of total body mass), any defect in glucose entry into the muscle cells, caused by muscle IR, significantly affects whole body glucose disposition. Subsequently, IR in skeletal muscle favors hyperglycemia and increase the risk of type 2 diabetes [4]. The importance of estrogens and their effects mediated through ERa in insulin resistance was suggested by whole body ERa knock-out (KO) and muscle-specific ERa KO mice that are obese and insulin resistant [5,6]. A negative association between muscle ERa expression and fat mass or insulinemia is observed in women and in genetically obese mice emphasizing the importance of muscle ERa signaling in insulin sensitivity [6]. Thus, the alterations resulting from reduced muscle ERa activity is important to consider to better understand mechanisms leading to muscle insulin resistance. Decreased mitochondrial oxidative capacity, increased production of reactive oxygen species and impaired insulin signaling should be considered as they are known to be key features of insulin-resistant muscle [7] and are also present in ERa KO mice [5,6].   Thus, the AOP that we propose here links the inactivation of ERa in skeletal muscle to one of the hallmarks of the metabolic syndrome that is insulin resistance taking account the following events “decreased mitochondrial fatty acid oxidation”, “increased reactive oxygen species”, “mitochondrial dysfunction”, “increased oxidative stress” and “impaired insulin signaling”.

adjacent

Not Specified

High adjacent

Not Specified

High adjacent

Not Specified

High adjacent

Not Specified

High adjacent

Not Specified

Moderate adjacent

Not Specified

High adjacent

Not Specified

High adjacent

Not Specified

High adjacent

Not Specified

High

<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td> </td> <td> </td> <td> </td> </tr> </tbody> </table> </div>

[1]       M.C. Carr, The emergence of the metabolic syndrome with menopause, J Clin Endocrinol Metab. 88 (2003) 2404–2411. https://doi.org/10.1210/jc.2003-030242. [2]       F. Mauvais-Jarvis, J.E. Manson, J.C. Stevenson, V.A. Fonseca, Menopausal Hormone Therapy and Type 2 Diabetes Prevention: Evidence, Mechanisms, and Clinical Implications, Endocr Rev. 38 (2017) 173–188. https://doi.org/10.1210/er.2016-1146. [3]       V. Rochira, B. Madeo, L. Zirilli, G. Caffagni, L. Maffei, C. Carani, Oestradiol replacement treatment and glucose homeostasis in two men with congenital aromatase deficiency: evidence for a role of oestradiol and sex steroids imbalance on insulin sensitivity in men, Diabet Med. 24 (2007) 1491–1495. https://doi.org/10.1111/j.1464-5491.2007.02304.x. [4]       R.A. DeFronzo, D. Tripathy, Skeletal muscle insulin resistance is the primary defect in type 2 diabetes, Diabetes Care. 32 Suppl 2 (2009) S157-163. https://doi.org/10.2337/dc09-S302. [5]       V. Ribas, M.T.A. Nguyen, D.C. Henstridge, A.-K. Nguyen, S.W. Beaven, M.J. Watt, A.L. Hevener, Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERalpha-deficient mice, Am J Physiol Endocrinol Metab. 298 (2010) E304-319. https://doi.org/10.1152/ajpendo.00504.2009. [6]       V. Ribas, B.G. Drew, Z. Zhou, J. Phun, N.Y. Kalajian, T. Soleymani, P. Daraei, K. Widjaja, J. Wanagat, T.Q. de Aguiar Vallim, A.H. Fluitt, S. Bensinger, T. Le, C. Radu, J.P. Whitelegge, S.W. Beaven, P. Tontonoz, A.J. Lusis, B.W. Parks, L. Vergnes, K. Reue, H. Singh, J.C. Bopassa, L. Toro, E. Stefani, M.J. Watt, S. Schenk, T. Akerstrom, M. Kelly, B.K. Pedersen, S.C. Hewitt, K.S. Korach, A.L. Hevener, Skeletal muscle action of estrogen receptor α is critical for the maintenance of mitochondrial function and metabolic homeostasis in females, Sci Transl Med. 8 (2016) 334ra54. https://doi.org/10.1126/scitranslmed.aad3815. [7]       S. Di Meo, S. Iossa, P. Venditti, Skeletal muscle insulin resistance: role of mitochondria and other ROS sources, J Endocrinol. 233 (2017) R15–R42. https://doi.org/10.1530/JOE-16-0598.   AOPWiki 2023-05-25T08:44:03

2023-09-25T16:27:14