FREE SHIPPING over $40
OVER 10000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Home / Equine Research Bank / Cells / Trodusquemine (MSI-1436) Restores Metabolic Flexibility and ...
Cells2024; 13(2); doi: 10.3390/cells13020152

Trodusquemine (MSI-1436) Restores Metabolic Flexibility and Mitochondrial Dynamics in Insulin-Resistant Equine Hepatic Progenitor Cells (HPCs).

Abstract: Equine metabolic syndrome (EMS) is a significant global health concern in veterinary medicine. There is increasing interest in utilizing molecular agents to modulate hepatocyte function for potential clinical applications. Recent studies have shown promising results in inhibiting protein tyrosine phosphatase (PTP1B) to maintain cell function in various models. In this study, we investigated the effects of the inhibitor Trodusquemine (MSI-1436) on equine hepatic progenitor cells (HPCs) under lipotoxic conditions. We examined proliferative activity, glucose uptake, and mitochondrial morphogenesis. Our study found that MSI-1436 promotes HPC entry into the cell cycle and protects them from palmitate-induced apoptosis by regulating mitochondrial dynamics and biogenesis. MSI-1436 also increases glucose uptake and protects HPCs from palmitate-induced stress by reorganizing the cells' morphological architecture. Furthermore, our findings suggest that MSI-1436 enhances 2-NBDG uptake by increasing the expression of SIRT1, which is associated with liver insulin sensitivity. It also promotes mitochondrial dynamics by modulating mitochondria quantity and morphotype as well as increasing the expression of PINK1, MFN1, and MFN2. Our study provides evidence that MSI-1436 has a positive impact on equine hepatic progenitor cells, indicating its potential therapeutic value in treating EMS and insulin dysregulation.
Get Full Text
Publication Date: 2024-01-14 PubMed ID: 38247843PubMed Central: PMC10814577DOI: 10.3390/cells13020152Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research examines the effects of the inhibitor Trodusquemine (MSI-1436) on equine hepatic progenitor cells (HPCs) under conditions of high fat toxicity, with results indicating that MSI-1436 assists in maintaining cell function, promotes glucose absorption and protects cells from stress. Research suggests that MSI-1436 could potentially be used to treat Equine Metabolic Syndrome (EMS) and insulin dysregulation.

Introduction and Objectives

  • The study set out to examine the effects of Trodusquemine (a PTP1B inhibitor) on equine hepatic progenitor cells under lipotoxic conditions, conditions that are high in fat toxicity. This is part of an emerging area of research that seeks to modulate liver cell function for potential treatment applications, particularly in relation to Equine Metabolic Syndrome (EMS), a major health concern worldwide.
  • The main objective was to determine if this inhibitor can promote cell functionality, including cell cycle entry, facilitating glucose uptake, and regulating mitochondrial dynamics, under these detrimental conditions.

    • Methodology and Results

    • The investigators used a variety of laboratory techniques to observe changes in cellular activity and structure. They assessed these cells for signs of proliferation and glucose uptake, references of cell activity, and examined mitochondrial morphogenesis, which refers to changes in the form and structure of these cell powerhouses.
    • The results of these tests showed that in the presence of Trodusquemine, these cells are protected from apoptosis, or programmed cell death, induced by palmitate, a type of saturated fatty acid. These results suggest the reorganization of cellular architecture to protect cells from the effects of high levels of this fat.

      • Implication and Impact

      • The findings suggest that Trodusquemine enhances 2-NBDG uptake, a measure of glucose uptake, by increasing the expression of SIRT1, a protein associated with liver insulin sensitivity. This suggests Trodusquemine could play a role in improving glucose absorption in conditions of low insulin sensitivity such as EMS.
      • Additionally, the study found this inhibitor promotes mitochondrial dynamics, modulating mitochondria quantity and morphotype and increasing the expression of critical proteins like PINK1, MFN1, and MFN2 necessary for optimal mitochondrial function.
      • Conclusively, the authors propose that these findings indicate the potential therapeutic value of Trodusquemine in treating conditions like EMS and insulin dysregulation, as it is shown to have a positive impact on equine hepatic progenitor cell functionality in high fat conditions.

Cite This Article

APA
Qasem B, Dąbrowska A, Króliczewski J, Łyczko J, Marycz K. (2024). Trodusquemine (MSI-1436) Restores Metabolic Flexibility and Mitochondrial Dynamics in Insulin-Resistant Equine Hepatic Progenitor Cells (HPCs). Cells, 13(2). https://doi.org/10.3390/cells13020152

Publication

Cells
ISSN: 2073-4409
NlmUniqueID: 101600052
Country: Switzerland
Language: English
Volume: 13
Issue: 2

Researcher Affiliations

Qasem, Badr
  • Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375 Wrocław, Poland.
Dąbrowska, Agnieszka
  • Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375 Wrocław, Poland.
Króliczewski, Jarosław
  • Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375 Wrocław, Poland.
Łyczko, Jacek
  • Department of Food Chemistry and Biocatalysis, Wrocław University of Environmental and Life Sciences, 50-375 Wrocław, Poland.
Marycz, Krzysztof
  • Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375 Wrocław, Poland.
  • Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, CA 95516, USA.

MeSH Terms

  • Animals
  • Cholestanes
  • Glucose
  • Horses
  • Insulin / metabolism
  • Metabolic Syndrome
  • Mitochondrial Dynamics / drug effects
  • Palmitates
  • Spermine / analogs & derivatives
  • Insulin Resistance / physiology

Grant Funding

  • 2018/29/B/NZ7/02662 / National Science Center

Conflict of Interest Statement

The authors declare no conflict of interest.

References

This article includes 98 references
  1. Li Q, Gong Y, Wang Y, Liu B, Chu Y, Gui S, Zheng Y, Chen X. Sirt1 Promotes the Restoration of Hepatic Progenitor Cell (HPC)-Mediated Liver Fatty Injury in NAFLD Through Activating the Wnt/β-Catenin Signal Pathway. Front. Nutr. 2021;8:791861.
    doi: 10.3389/fnut.2021.791861pmc: PMC8714951pubmed: 34977130google scholar: lookup
  2. So J, Kim A, Lee S-H, Shin D. Liver Progenitor Cell-Driven Liver Regeneration. Exp. Mol. Med. 2020;52:1230–1238.
    doi: 10.1038/s12276-020-0483-0pmc: PMC8080804pubmed: 32796957google scholar: lookup
  3. Watt M.J, Miotto P.M, De Nardo W, Montgomery M.K. The Liver as an Endocrine Organ—Linking NAFLD and Insulin Resistance. Endocr. Rev. 2019;40:1367–1393.
    doi: 10.1210/er.2019-00034pubmed: 31098621google scholar: lookup
  4. Xu Y.Q, Liu Z.C. Therapeutic Potential of Adult Bone Marrow Stem Cells in Liver Disease and Delivery Approaches. Stem Cell Rev. 2008;4:101–112.
    doi: 10.1007/s12015-008-9019-zpubmed: 18481229google scholar: lookup
  5. Bourebaba L, Komakula S.S.B, Weiss C, Adrar N, Marycz K. The PTP1B Selective Inhibitor MSI-1436 Mitigates Tunicamycin-Induced ER Stress in Human Hepatocarcinoma Cell Line through XBP1 Splicing Modulation. PLoS ONE 2023;18:e0278566.
    doi: 10.1371/journal.pone.0278566pmc: PMC9844924pubmed: 36649358google scholar: lookup
  6. Marycz K, Szłapka-Kosarzewska J, Geburek F, Kornicka-Garbowska K. Systemic Administration of Rejuvenated Adipose-Derived Mesenchymal Stem Cells Improves Liver Metabolism in Equine Metabolic Syndrome (EMS)- New Approach in Veterinary Regenerative Medicine. Stem Cell Rev. Rep. 2019;15:842–850.
    doi: 10.1007/s12015-019-09913-3pmc: PMC6925066pubmed: 31620992google scholar: lookup
  7. Marycz K, Bourebaba N, Serwotka-Suszczak A, Mularczyk M, Galuppo L, Bourebaba L. In Vitro Generated Equine Hepatic-Like Progenitor Cells as a Novel Potent Cell Pool for Equine Metabolic Syndrome (EMS) Treatment. Stem Cell Rev. Rep. 2023;9:1124–1134.
    doi: 10.1007/s12015-023-10507-3pmc: PMC10185601pubmed: 36658383google scholar: lookup
  8. Roskams T, Yang S.Q, Koteish A, Durnez A, DeVos R, Huang X, Achten R, Verslype C, Diehl A.M. Oxidative Stress and Oval Cell Accumulation in Mice and Humans with Alcoholic and Nonalcoholic Fatty Liver Disease. Am. J. Pathol. 2003;163:1301–1311.
    doi: 10.1016/S0002-9440(10)63489-Xpmc: PMC1868311pubmed: 14507639google scholar: lookup
  9. Bria A, Marda J, Zhou J, Sun X, Cao Q, Petersen B.E, Pi L. Hepatic Progenitor Cell Activation in Liver Repair. Liver Res. 2017;1:81–87.
    doi: 10.1016/j.livres.2017.08.002pmc: PMC5739327pubmed: 29276644google scholar: lookup
  10. Ozaki M. Cellular and Molecular Mechanisms of Liver Regeneration: Proliferation, Growth, Death and Protection of Hepatocytes. Semin. Cell Dev. Biol. 2020;100:62–73.
    doi: 10.1016/j.semcdb.2019.10.007pubmed: 31669133google scholar: lookup
  11. Alicka M, Kornicka-Garbowska K, Roecken M, Marycz K. Inhibition of the Low Molecular Weight Protein Tyrosine Phosphatase (LMPTP) as a Potential Therapeutic Strategy for Hepatic Progenitor Cells Lipotoxicity—Short Communication. Int. J. Mol. Sci. 2019;20:5873.
    doi: 10.3390/ijms20235873pmc: PMC6928870pubmed: 31771123google scholar: lookup
  12. Frank N, Geor R.J, Bailey S.R, Durham A.E, Johnson P.J. Equine Metabolic Syndrome. J. Vet. Intern. Med. 2010;24:467–475.
    doi: 10.1111/j.1939-1676.2010.0503.xpubmed: 20384947google scholar: lookup
  13. Johnson T.O, Ermolieff J, Jirousek M.R. Protein Tyrosine Phosphatase 1B Inhibitors for Diabetes. Nat. Rev. Drug Discov. 2002;1:696–709.
    doi: 10.1038/nrd895pubmed: 12209150google scholar: lookup
  14. Ibrahim S.H, Kohli R, Gores G.J. Mechanisms of Lipotoxicity in NAFLD and Clinical Implications. J. Pediatr. Gastroenterol. Nutr. 2011;53:131–140.
    doi: 10.1097/MPG.0b013e31822578dbpmc: PMC3145329pubmed: 21629127google scholar: lookup
  15. Boucher J, Kleinridders A, Kahn C.R. Insulin Receptor Signaling in Normal and Insulin-Resistant States. Cold Spring Harb. Perspect. Biol. 2014;6:a009191.
    doi: 10.1101/cshperspect.a009191pmc: PMC3941218pubmed: 24384568google scholar: lookup
  16. Kaczmarek K, Janicki B, Głowska M. Insulin Resistance in the Horse: A Review. J. Appl. Anim. Res. 2016;44:424–430.
    doi: 10.1080/09712119.2015.1091340google scholar: lookup
  17. Alicka M, Marycz K. The Effect of Chronic Inflammation and Oxidative and Endoplasmic Reticulum Stress in the Course of Metabolic Syndrome and Its Therapy. Stem Cells Int. 2018;2018:e4274361.
    doi: 10.1155/2018/4274361pmc: PMC6217741pubmed: 30425746google scholar: lookup
  18. Marycz K, Kornicka K, Szlapka-Kosarzewska J, Weiss C. Excessive Endoplasmic Reticulum Stress Correlates with Impaired Mitochondrial Dynamics, Mitophagy and Apoptosis, in Liver and Adipose Tissue, but Not in Muscles in EMS Horses. Int. J. Mol. Sci. 2018;19:165.
    doi: 10.3390/ijms19010165pmc: PMC5796114pubmed: 29316632google scholar: lookup
  19. Saltiel A.R, Kahn C.R. Insulin Signalling and the Regulation of Glucose and Lipid Metabolism. Nature 2001;414:799–806.
    doi: 10.1038/414799apubmed: 11742412google scholar: lookup
  20. Leturque A, Brot-Laroche E, Le Gall M, Stolarczyk E, Tobin V. The Role of GLUT2 in Dietary Sugar Handling. J. Physiol. Biochem. 2006;61:529–537.
    doi: 10.1007/BF03168378pubmed: 16669350google scholar: lookup
  21. Pilkis S.J, Granner D.K. Molecular Physiology of the Regulation of Hepatic Gluconeogenesis and Glycolysis. Annu. Rev. Physiol. 1992;54:885–909.
    doi: 10.1146/annurev.ph.54.030192.004321pubmed: 1562196google scholar: lookup
  22. Kemper J.K, Choi S-E, Kim D.H. Sirtuin 1 Deacetylase: A Key Regulator of Hepatic Lipid Metabolism. Vitamins & Hormones 2013;91:385–404.
    pmc: PMC4976444pubmed: 23374725
  23. Li Y, Wong K, Giles A, Jiang J, Lee J.W, Adams A.C, Kharitonenkov A, Yang Q, Gao B, Guarente L. Hepatic SIRT1 Attenuates Hepatic Steatosis and Controls Energy Balance in Mice by Inducing Fibroblast Growth Factor 21. Gastroenterology 2014;146:539–549.e7.
    doi: 10.1053/j.gastro.2013.10.059pmc: PMC4228483pubmed: 24184811google scholar: lookup
  24. Zhang S, Cai G, Fu B, Feng Z, Ding R, Bai X, Liu W, Zhuo L, Sun L, Liu F. SIRT1 Is Required for the Effects of Rapamycin on High Glucose-Inducing Mesangial Cells Senescence. Mech. Ageing Dev. 2012;133:387–400.
    doi: 10.1016/j.mad.2012.04.005pubmed: 22561310google scholar: lookup
  25. Ghosh H.S, McBurney M, Robbins P.D. SIRT1 Negatively Regulates the Mammalian Target of Rapamycin. PLoS ONE 2010;5:e9199.
    doi: 10.1371/journal.pone.0009199pmc: PMC2821410pubmed: 20169165google scholar: lookup
  26. Bourebaba L, Łyczko J, Alicka M, Bourebaba N, Szumny A, Fal A.M, Marycz K. Inhibition of Protein-Tyrosine Phosphatase PTP1B and LMPTP Promotes Palmitate/Oleate-Challenged HepG2 Cell Survival by Reducing Lipoapoptosis, Improving Mitochondrial Dynamics and Mitigating Oxidative and Endoplasmic Reticulum Stress. J. Clin. Med. 2020;9:1294.
    doi: 10.3390/jcm9051294pmc: PMC7288314pubmed: 32369900google scholar: lookup
  27. Chen P-J, Cai S-P, Yang Y, Li W-X, Huang C, Meng X-M, Li J. PTP1B Confers Liver Fibrosis by Regulating the Activation of Hepatic Stellate Cells. Toxicol. Appl. Pharmacol. 2016;292:8–18.
    doi: 10.1016/j.taap.2015.12.021pubmed: 26739621google scholar: lookup
  28. Lantz K.A, Hart S.G.E, Planey S.L, Roitman M.F, Ruiz-White I.A, Wolfe H.R, McLane M.P. Inhibition of PTP1B by Trodusquemine (MSI-1436) Causes Fat-Specific Weight Loss in Diet-Induced Obese Mice. Obesity 2010;18:1516–1523.
    doi: 10.1038/oby.2009.444pubmed: 20075852google scholar: lookup
  29. Bourebaba L, Kornicka-Garbowska K, Al Naem M, Röcken M, Łyczko J, Marycz K. MSI-1436 Improves EMS Adipose Derived Progenitor Stem Cells in the Course of Adipogenic Differentiation through Modulation of ER Stress, Apoptosis, and Oxidative Stress. Stem Cell Res. Ther. 2021;12:97.
    doi: 10.1186/s13287-020-02102-xpmc: PMC7860037pubmed: 33536069google scholar: lookup
  30. Arnold I, Langer T. Membrane Protein Degradation by AAA Proteases in Mitochondria. Biochim. Biophys. Acta 2002;1592:89–96.
    doi: 10.1016/S0167-4889(02)00267-7pubmed: 12191771google scholar: lookup
  31. Chen H, Chan D.C. Physiological Functions of Mitochondrial Fusion. Ann. N. Y. Acad. Sci. 2010;1201:21–25.
    doi: 10.1111/j.1749-6632.2010.05615.xpubmed: 20649534google scholar: lookup
  32. Narendra D.P, Youle R.J. Targeting Mitochondrial Dysfunction: Role for PINK1 and Parkin in Mitochondrial Quality Control. Antioxid. Redox Signal. 2011;14:1929–1938.
    doi: 10.1089/ars.2010.3799pmc: PMC3078490pubmed: 21194381google scholar: lookup
  33. Narendra D, Tanaka A, Suen D-F, Youle R.J. Parkin Is Recruited Selectively to Impaired Mitochondria and Promotes Their Autophagy. J. Cell Biol. 2008;183:795–803.
    doi: 10.1083/jcb.200809125pmc: PMC2592826pubmed: 19029340google scholar: lookup
  34. Wu W, Xu H, Wang Z, Mao Y, Yuan L, Luo W, Cui Z, Cui T, Wang X.L, Shen Y.H. PINK1-Parkin-Mediated Mitophagy Protects Mitochondrial Integrity and Prevents Metabolic Stress-Induced Endothelial Injury. PLoS ONE 2015;10:e0132499.
    doi: 10.1371/journal.pone.0132499pmc: PMC4498619pubmed: 26161534google scholar: lookup
  35. Moreira O.C, Estébanez B, Martínez-Florez S, de Paz J.A, Cuevas M.J, González-Gallego J. Mitochondrial Function and Mitophagy in the Elderly: Effects of Exercise. Oxid. Med. Cell Longev. 2017;2017:2012798.
    doi: 10.1155/2017/2012798pmc: PMC5576425pubmed: 28900532google scholar: lookup
  36. Ma X, McKeen T, Zhang J, Ding W-X. Role and Mechanisms of Mitophagy in Liver Diseases. Cells 2020;9:837.
    doi: 10.3390/cells9040837pmc: PMC7226762pubmed: 32244304google scholar: lookup
  37. Wang R, Zhu Y, Lin X, Ren C, Zhao J, Wang F, Gao X, Xiao R, Zhao L, Chen H. Influenza M2 Protein Regulates MAVS-Mediated Signaling Pathway through Interacting with MAVS and Increasing ROS Production. Autophagy 2019;15:1163–1181.
    doi: 10.1080/15548627.2019.1580089pmc: PMC6613841pubmed: 30741586google scholar: lookup
  38. Bradshaw A.V, Campbell P, Schapira A.H.V, Morris H.R, Taanman J-W. The PINK1—Parkin Mitophagy Signalling Pathway Is Not Functional in Peripheral Blood Mononuclear Cells. PLoS ONE 2021;16:e0259903.
    doi: 10.1371/journal.pone.0259903pmc: PMC8584748pubmed: 34762687google scholar: lookup
  39. Taléns-Visconti R. Hepatogenic Differentiation of Human Mesenchymal Stem Cells from Adipose Tissue in Comparison with Bone Marrow Mesenchymal Stem Cells. WJG 2006;12:5834.
    doi: 10.3748/wjg.v12.i36.5834pmc: PMC4100665pubmed: 17007050google scholar: lookup
  40. Yang M, Wei D, Mo C, Zhang J, Wang X, Han X, Wang Z, Xiao H. Saturated Fatty Acid Palmitate-Induced Insulin Resistance Is Accompanied with Myotube Loss and the Impaired Expression of Health Benefit Myokine Genes in C2C12 Myotubes. Lipids Health Dis. 2013;12:104.
    doi: 10.1186/1476-511X-12-104pmc: PMC3723881pubmed: 23866690google scholar: lookup
  41. Marycz K, Śmieszek A, Grzesiak J, Donesz-Sikorska A, Krzak-Roś J. Application of Bone Marrow and Adipose-Derived Mesenchymal Stem Cells for Testing the Biocompatibility of Metal-Based Biomaterials Functionalized with Ascorbic Acid. Biomed. Mater. 2013;8:065004.
    doi: 10.1088/1748-6041/8/6/065004pubmed: 24280658google scholar: lookup
  42. Bourebaba L, Bedjou F, Röcken M, Marycz K. Nortropane Alkaloids as Pharmacological Chaperones in the Rescue of Equine Adipose-Derived Mesenchymal Stromal Stem Cells Affected by Metabolic Syndrome through Mitochondrial Potentiation, Endoplasmic Reticulum Stress Mitigation and Insulin Resistance Alleviation. Stem Cell Res. Ther. 2019;10:178.
    doi: 10.1186/s13287-019-1292-zpmc: PMC6582509pubmed: 31215461google scholar: lookup
  43. Bai J, Wang M.X, Chowbay B, Ching C.B, Chen W.N. Metabolic Profiling of HepG2 Cells Incubated with S(−) and R(+) Enantiomers of Anti-Coagulating Drug Warfarin. Metabolomics 2011;7:353–362.
    doi: 10.1007/s11306-010-0262-3pmc: PMC3155677pubmed: 21949493google scholar: lookup
  44. Peng J-Y, Lin C-C, Chen Y-J, Kao L-S, Liu Y-C, Chou C-C, Huang Y-H, Chang F-R, Wu Y-C, Tsai Y-S. Automatic Morphological Subtyping Reveals New Roles of Caspases in Mitochondrial Dynamics. PLoS Comput. Biol. 2011;7:e1002212.
    doi: 10.1371/journal.pcbi.1002212pmc: PMC3188504pubmed: 21998575google scholar: lookup
  45. Kornicka-Garbowska K, Bourebaba L, Röcken M, Marycz K. Inhibition of Protein Tyrosine Phosphatase Improves Mitochondrial Bioenergetics and Dynamics, Reduces Oxidative Stress, and Enhances Adipogenic Differentiation Potential in Metabolically Impaired Progenitor Stem Cells. Cell Commun. Signal. 2021;19:106.
    doi: 10.1186/s12964-021-00772-5pmc: PMC8565043pubmed: 34732209google scholar: lookup
  46. Weiss C, Kornicka-Grabowska K, Mularczyk M, Siwinska N, Marycz K. Extracellular Microvesicles (MV’s) Isolated from 5-Azacytidine-and-Resveratrol-Treated Cells Improve Viability and Ameliorate Endoplasmic Reticulum Stress in Metabolic Syndrome Derived Mesenchymal Stem Cells. Stem Cell Rev. Rep. 2020;16:1343–1355.
    doi: 10.1007/s12015-020-10035-4pmc: PMC7667134pubmed: 32880856google scholar: lookup
  47. Antonsson B, Conti F, Ciavatta A, Montessuit S, Lewis S, Martinou I, Bernasconi L, Bernard A, Mermod J-J, Mazzei G. Inhibition of Bax Channel-Forming Activity by Bcl-2. Science 1997;277:370–372.
    doi: 10.1126/science.277.5324.370pubmed: 9219694google scholar: lookup
  48. Zhou B, Li C, Qi W, Zhang Y, Zhang F, Wu J.X, Hu Y.N, Wu D.M, Liu Y, Yan T.T. Downregulation of miR-181a Upregulates Sirtuin-1 (SIRT1) and Improves Hepatic Insulin Sensitivity. Diabetologia 2012;55:2032–2043.
    doi: 10.1007/s00125-012-2539-8pubmed: 22476949google scholar: lookup
  49. Prabhakar P.K, Sivakumar P.M. Protein Tyrosine Phosphatase 1B Inhibitors: A Novel Therapeutic Strategy for the Management of Type 2 Diabetes Mellitus. Curr. Pharm. Des. 2019;25:2526–2539.
    doi: 10.2174/1381612825666190716102901pubmed: 31333090google scholar: lookup
  50. Chiarugi P, Buricchi F. Protein Tyrosine Phosphorylation and Reversible Oxidation: Two Cross-Talking Posttranslation Modifications. Antioxid. Redox Signal. 2007;9:1–24.
    doi: 10.1089/ars.2007.9.1pubmed: 17115885google scholar: lookup
  51. Shimizu S, Ugi S, Maegawa H, Egawa K, Nishio Y, Yoshizaki T, Shi K, Nagai Y, Morino K, Nemoto K. Protein-Tyrosine Phosphatase 1B as New Activator for Hepatic Lipogenesis via Sterol Regulatory Element-Binding Protein-1 Gene Expression. J. Biol. Chem. 2003;278:43095–43101.
    doi: 10.1074/jbc.M306880200pubmed: 12941932google scholar: lookup
  52. Taghibiglou C, Rashid-Kolvear F, Van Iderstine S.C, Le-Tien H, Fantus I.G, Lewis G.F, Adeli K. Hepatic Very Low Density Lipoprotein-ApoB Overproduction Is Associated with Attenuated Hepatic Insulin Signaling and Overexpression of Protein-Tyrosine Phosphatase 1B in a Fructose-Fed Hamster Model of Insulin Resistance. J. Biol. Chem. 2002;277:793–803.
    doi: 10.1074/jbc.M106737200pubmed: 11598116google scholar: lookup
  53. Zabolotny J.M, Kim Y-B, Welsh L.A, Kershaw E.E, Neel B.G, Kahn B.B. Protein-Tyrosine Phosphatase 1B Expression Is Induced by Inflammation in Vivo. J. Biol. Chem. 2008;283:14230–14241.
    doi: 10.1074/jbc.M800061200pmc: PMC2386946pubmed: 18281274google scholar: lookup
  54. Agouni A, Mody N, Owen C, Czopek A, Zimmer D, Bentires-Alj M, Bence K.K, Delibegović M. Liver-Specific Deletion of Protein Tyrosine Phosphatase (PTP) 1B Improves Obesity- and Pharmacologically Induced Endoplasmic Reticulum Stress. Biochem. J. 2011;438:369–378.
    doi: 10.1042/BJ20110373pmc: PMC3744093pubmed: 21605081google scholar: lookup
  55. Chen P-J, Cai S-P, Huang C, Meng X-M, Li J. Protein Tyrosine Phosphatase 1B (PTP1B): A Key Regulator and Therapeutic Target in Liver Diseases. Toxicology 2015;337:10–20.
    doi: 10.1016/j.tox.2015.08.006pubmed: 26299811google scholar: lookup
  56. Anderson S.M, Cheesman H.K, Peterson N.D, Salisbury J.E, Soukas A.A, Pukkila-Worley R. The Fatty Acid Oleate Is Required for Innate Immune Activation and Pathogen Defense in Caenorhabditis Elegans. PLoS Pathog. 2019;15:e1007893.
    doi: 10.1371/journal.ppat.1007893pmc: PMC6597122pubmed: 31206555google scholar: lookup
  57. Baylin A, Kabagambe E.K, Siles X, Campos H. Adipose Tissue Biomarkers of Fatty Acid Intake. Am. J. Clin. Nutr. 2002;76:750–757.
    doi: 10.1093/ajcn/76.4.750pubmed: 12324287google scholar: lookup
  58. Hirsova P, Ibrabim S.H, Gores G.J, Malhi H. Lipotoxic Lethal and Sublethal Stress Signaling in Hepatocytes: Relevance to NASH Pathogenesis. J. Lipid Res. 2016;57:1758–1770.
    doi: 10.1194/jlr.R066357pmc: PMC5036373pubmed: 27049024google scholar: lookup
  59. Hanayama M, Yamamoto Y, Utsunomiya H, Yoshida O, Liu S, Mogi M, Matsuura B, Takeshita E, Ikeda Y, Hiasa Y. The Mechanism of Increased Intestinal Palmitic Acid Absorption and Its Impact on Hepatic Stellate Cell Activation in Nonalcoholic Steatohepatitis. Sci. Rep. 2021;11:13380.
    doi: 10.1038/s41598-021-92790-zpmc: PMC8239050pubmed: 34183709google scholar: lookup
  60. Chen L, Teng H, Cao H. Chlorogenic Acid and Caffeic Acid from Sonchus Oleraceus Linn Synergistically Attenuate Insulin Resistance and Modulate Glucose Uptake in HepG2 Cells. Food Chem. Toxicol. 2019;127:182–187.
    doi: 10.1016/j.fct.2019.03.038pubmed: 30914352google scholar: lookup
  61. Charytoniuk T, Iłowska N, Berk K, Drygalski K, Chabowski A, Konstantynowicz-Nowicka K. The Effect of Enterolactone on Sphingolipid Pathway and Hepatic Insulin Resistance Development in HepG2 Cells. Life Sci. 2019;217:1–7.
    doi: 10.1016/j.lfs.2018.11.044pubmed: 30468835google scholar: lookup
  62. Obanda D.N, Hernandez A, Ribnicky D, Yu Y, Zhang X.H, Wang Z.Q, Cefalu W.T. Bioactives of Artemisia Dracunculus L. Mitigate the Role of Ceramides in Attenuating Insulin Signaling in Rat Skeletal Muscle Cells. Diabetes 2012;61:597–605.
    doi: 10.2337/db11-0396pmc: PMC3282822pubmed: 22315320google scholar: lookup
  63. Obanda D.N, Cefalu W.T. Modulation of Cellular Insulin Signaling and PTP1B Effects by Lipid Metabolites in Skeletal Muscle Cells. J. Nutr. Biochem. 2013;24:1529–1537.
    doi: 10.1016/j.jnutbio.2012.12.014pmc: PMC4509740pubmed: 23481236google scholar: lookup
  64. Batista T.M, Haider N, Kahn C.R. Defining the Underlying Defect in Insulin Action in Type 2 Diabetes. Diabetologia 2021;64:994–1006.
    doi: 10.1007/s00125-021-05415-5pmc: PMC8916220pubmed: 33730188google scholar: lookup
  65. Sharma B.R, Kim H.J, Rhyu D.Y. Caulerpa Lentillifera Extract Ameliorates Insulin Resistance and Regulates Glucose Metabolism in C57BL/KsJ-Db/Db Mice via PI3K/AKT Signaling Pathway in Myocytes. J. Transl. Med. 2015;13:62.
    doi: 10.1186/s12967-015-0412-5pmc: PMC4350654pubmed: 25889508google scholar: lookup
  66. Carr R.M, Correnti J. Insulin Resistance in Clinical and Experimental Alcoholic Liver Disease. Ann. N. Y. Acad. Sci. 2015;1353:1–20.
    doi: 10.1111/nyas.12787pmc: PMC4623941pubmed: 25998863google scholar: lookup
  67. Beurel E, Grieco S.F, Jope R.S. Glycogen Synthase Kinase-3 (GSK3): Regulation, Actions, and Diseases. Pharmacol. Ther. 2015;148:114–131.
    doi: 10.1016/j.pharmthera.2014.11.016pmc: PMC4340754pubmed: 25435019google scholar: lookup
  68. Ghanem A, Kitanovic A, Holzwarth J, Wölfl S. Mutational Analysis of Fructose-1,6-Bis-Phosphatase FBP1 Indicates Partially Independent Functions in Gluconeogenesis and Sensitivity to Genotoxic Stress. Microb. Cell. 2017;4:52–63.
    doi: 10.15698/mic2017.02.557pmc: PMC5349122pubmed: 28357389google scholar: lookup
  69. Gross D.N, Wan M, Birnbaum M.J. The Role of FOXO in the Regulation of Metabolism. Curr. Diab Rep. 2009;9:208–214.
    doi: 10.1007/s11892-009-0034-5pubmed: 19490822google scholar: lookup
  70. Naowaboot J, Piyabhan P, Munkong N, Parklak W, Pannangpetch P. Ferulic Acid Improves Lipid and Glucose Homeostasis in High-Fat Diet-Induced Obese Mice. Clin. Exp. Pharmacol. Physiol. 2016;43:242–250.
    doi: 10.1111/1440-1681.12514pubmed: 26541794google scholar: lookup
  71. Shao W, Espenshade P.J. Expanding Roles for SREBP in Metabolism. Cell Metab. 2012;16:414–419.
    doi: 10.1016/j.cmet.2012.09.002pmc: PMC3466394pubmed: 23000402google scholar: lookup
  72. Xuguang H, Aofei T, Tao L, Longyan Z, Weijian B, Jiao G. Hesperidin Ameliorates Insulin Resistance by Regulating the IRS1-GLUT2 Pathway via TLR4 in HepG2 Cells. Phytother. Res. 2019;33:1697–1705.
    doi: 10.1002/ptr.6358pubmed: 31074547google scholar: lookup
  73. Thorens B. GLUT2, Glucose Sensing and Glucose Homeostasis. Diabetologia 2015;58:221–232.
    doi: 10.1007/s00125-014-3451-1pubmed: 25421524google scholar: lookup
  74. Huang F, Chen J, Wang J, Zhu P, Lin W. Palmitic Acid Induces MicroRNA-221 Expression to Decrease Glucose Uptake in HepG2 Cells via the PI3K/AKT/GLUT4 Pathway. Biomed. Res. Int. 2019;2019:8171989.
    doi: 10.1155/2019/8171989pmc: PMC6885153pubmed: 31828133google scholar: lookup
  75. Erion D.M, Yonemitsu S, Nie Y, Nagai Y, Gillum M.P, Hsiao J.J, Iwasaki T, Stark R, Weismann D, Yu X.X. SirT1 Knockdown in Liver Decreases Basal Hepatic Glucose Production and Increases Hepatic Insulin Responsiveness in Diabetic Rats. Proc. Natl. Acad. Sci. USA 2009;106:11288–11293.
    doi: 10.1073/pnas.0812931106pmc: PMC2700142pubmed: 19549853google scholar: lookup
  76. Gupte R.S, Floyd B.C, Kozicky M, George S, Ungvari Z.I, Neito V, Wolin M.S, Gupte S.A. Synergistic Activation of Glucose-6-Phosphate Dehydrogenase and NAD(P)H Oxidase by Src Kinase Elevates Superoxide in Type 2 Diabetic, Zucker Fa/Fa, Rat Liver. Free Radic. Biol. Med. 2009;47:219–228.
    doi: 10.1016/j.freeradbiomed.2009.01.028pmc: PMC2700195pubmed: 19230846google scholar: lookup
  77. You M, Liang X, Ajmo J.M, Ness G.C. Involvement of Mammalian Sirtuin 1 in the Action of Ethanol in the Liver. Am. J. Physiol. Gastrointest. Liver Physiol. 2008;294:G892–G898.
    doi: 10.1152/ajpgi.00575.2007pubmed: 18239056google scholar: lookup
  78. Ponugoti B, Kim D-H, Xiao Z, Smith Z, Miao J, Zang M, Wu S-Y, Chiang C-M, Veenstra T.D, Kemper J.K. SIRT1 Deacetylates and Inhibits SREBP-1C Activity in Regulation of Hepatic Lipid Metabolism. J. Biol. Chem. 2010;285:33959–33970.
    doi: 10.1074/jbc.M110.122978pmc: PMC2962496pubmed: 20817729google scholar: lookup
  79. Walker A.K, Yang F, Jiang K, Ji J-Y, Watts J.L, Purushotham A, Boss O, Hirsch M.L, Ribich S, Smith J.J. Conserved Role of SIRT1 Orthologs in Fasting-Dependent Inhibition of the Lipid/Cholesterol Regulator SREBP. Genes. Dev. 2010;24:1403–1417.
    doi: 10.1101/gad.1901210pmc: PMC2895199pubmed: 20595232google scholar: lookup
  80. Morton J.D, Shimomura L. Sterol Regulatory Element-Binding Proteins: Activators of Cholesterol and Fatty Acid Biosynthesis. Curr. Opin. Lipidol. 1999;10:143.
    doi: 10.1097/00041433-199904000-00008pubmed: 10327282google scholar: lookup
  81. Osborne T.F. Sterol Regulatory Element-Binding Proteins (SREBPs): Key Regulators of Nutritional Homeostasis and Insulin Action. J. Biol. Chem. 2000;275:32379–32382.
    doi: 10.1074/jbc.R000017200pubmed: 10934219google scholar: lookup
  82. Gulick T, Cresci S, Caira T, Moore D.D, Kelly D.P. The Peroxisome Proliferator-Activated Receptor Regulates Mitochondrial Fatty Acid Oxidative Enzyme Gene Expression. Proc. Natl. Acad. Sci. USA 1994;91:11012–11016.
    doi: 10.1073/pnas.91.23.11012pmc: PMC45156pubmed: 7971999google scholar: lookup
  83. Rodgers J.T, Lerin C, Gerhart-Hines Z, Puigserver P. Metabolic Adaptations through the PGC-1α and SIRT1 Pathways. FEBS Lett. 2008;582:46–53.
    doi: 10.1016/j.febslet.2007.11.034pmc: PMC2275806pubmed: 18036349google scholar: lookup
  84. Yu G-S, Lu Y-C, Gulick T. Co-Regulation of Tissue-Specific Alternative Human Carnitine Palmitoyltransferase Iβ Gene Promoters by Fatty Acid Enzyme Substrate. J. Biol. Chem. 1998;273:32901–32909.
    doi: 10.1074/jbc.273.49.32901pubmed: 9830040google scholar: lookup
  85. Lan F, Cacicedo J.M, Ruderman N, Ido Y. SIRT1 Modulation of the Acetylation Status, Cytosolic Localization, and Activity of LKB1: Possible Role in AMP-Activated Protein Kinase Activation. J. Biol. Chem. 2008;283:27628–27635.
    doi: 10.1074/jbc.M805711200pmc: PMC2562073pubmed: 18687677google scholar: lookup
  86. Stümpel F, Burcelin R, Jungermann K, Thorens B. Normal Kinetics of Intestinal Glucose Absorption in the Absence of GLUT2: Evidence for a Transport Pathway Requiring Glucose Phosphorylation and Transfer into the Endoplasmic Reticulum. Proc. Natl. Acad. Sci. USA 2001;98:11330–11335.
    doi: 10.1073/pnas.211357698pmc: PMC58729pubmed: 11562503google scholar: lookup
  87. Guillam M-T, Burcelin R, Thorens B. Normal Hepatic Glucose Production in the Absence of GLUT2 Reveals an Alternative Pathway for Glucose Release from Hepatocytes. Proc. Natl. Acad. Sci. USA 1998;95:12317–12321.
    doi: 10.1073/pnas.95.21.12317pmc: PMC22829pubmed: 9770484google scholar: lookup
  88. Burcelin R, del Carmen Muñoz M, Guillam M-T, Thorens B. Liver Hyperplasia and Paradoxical Regulation of Glycogen Metabolism and Glucose-Sensitive Gene Expression in GLUT2-Null Hepatocytes: Further Evidence for the Existence of A Membrane-Based Glucose Release Pathway. J. Biol. Chem. 2000;275:10930–10936.
    doi: 10.1074/jbc.275.15.10930pubmed: 10753892google scholar: lookup
  89. Rachek L.I, Musiyenko S.I, LeDoux S.P, Wilson G.L. Palmitate Induced Mitochondrial Deoxyribonucleic Acid Damage and Apoptosis in L6 Rat Skeletal Muscle Cells. Endocrinology 2007;148:293–299.
    doi: 10.1210/en.2006-0998pubmed: 17023529google scholar: lookup
  90. Yuzefovych L.V, Solodushko V.A, Wilson G.L, Rachek L.I. Protection from Palmitate-Induced Mitochondrial DNA Damage Prevents from Mitochondrial Oxidative Stress, Mitochondrial Dysfunction, Apoptosis, and Impaired Insulin Signaling in Rat L6 Skeletal Muscle Cells. Endocrinology 2012;153:92–100.
    doi: 10.1210/en.2011-1442pmc: PMC3249685pubmed: 22128025google scholar: lookup
  91. Gao X, Zhao X, Zhu Y, Li X, Xu Q, Lin H, Wang M. Tetramethylpyrazine Protects Palmitate-Induced Oxidative Damage and Mitochondrial Dysfunction in C2C12 Myotubes. Life Sci. 2011;88:803–809.
    doi: 10.1016/j.lfs.2011.02.025pubmed: 21396380google scholar: lookup
  92. Wang Z, Hou L, Huang L, Guo J, Zhou X. Exenatide Improves Liver Mitochondrial Dysfunction and Insulin Resistance by Reducing Oxidative Stress in High Fat Diet-Induced Obese Mice. Biochem. Biophys. Res. Commun. 2017;486:116–123.
    doi: 10.1016/j.bbrc.2017.03.010pubmed: 28274877google scholar: lookup
  93. Wang J, Zou Q, Suo Y, Tan X, Yuan T, Liu Z, Liu X. Lycopene Ameliorates Systemic Inflammation-Induced Synaptic Dysfunction via Improving Insulin Resistance and Mitochondrial Dysfunction in the Liver-Brain Axis. Food Funct. 2019;10:2125–2137.
    doi: 10.1039/C8FO02460Jpubmed: 30924473google scholar: lookup
  94. Li G, Yang J, Yang C, Zhu M, Jin Y, McNutt M.A, Yin Y. PTENα Regulates Mitophagy and Maintains Mitochondrial Quality Control. Autophagy 2018;14:1742–1760.
    doi: 10.1080/15548627.2018.1489477pmc: PMC6135630pubmed: 29969932google scholar: lookup
  95. Redmann M, Benavides G.A, Wani W.Y, Berryhill T.F, Ouyang X, Johnson M.S, Ravi S, Mitra K, Barnes S, Darley-Usmar V.M. Methods for Assessing Mitochondrial Quality Control Mechanisms and Cellular Consequences in Cell Culture. Redox Biol. 2018;17:59–69.
    doi: 10.1016/j.redox.2018.04.005pmc: PMC6006680pubmed: 29677567google scholar: lookup
  96. Wang N, Liu Y, Ma Y, Wen D. Hydroxytyrosol Ameliorates Insulin Resistance by Modulating Endoplasmic Reticulum Stress and Prevents Hepatic Steatosis in Diet-Induced Obesity Mice. J. Nutr. Biochem. 2018;57:180–188.
    doi: 10.1016/j.jnutbio.2018.03.018pubmed: 29747118google scholar: lookup
  97. Su Z, Nie Y, Huang X, Zhu Y, Feng B, Tang L, Zheng G. Mitophagy in Hepatic Insulin Resistance: Therapeutic Potential and Concerns. Front. Pharmacol. 2019;10:1193.
    doi: 10.3389/fphar.2019.01193pmc: PMC6795753pubmed: 31649547google scholar: lookup
  98. Wang S, Chen X, Nair S, Sun D, Wang X, Ren J. Deletion of Protein Tyrosine Phosphatase 1B Obliterates Endoplasmic Reticulum Stress-Induced Myocardial Dysfunction through Regulation of Autophagy. Biochim. Et. Biophys. Acta (BBA) Mol. Basis Dis. 2017;1863:3060–3074.
    doi: 10.1016/j.bbadis.2017.09.015pubmed: 28941626google scholar: lookup

Citations

This article has been cited 2 times.
  1. Allen B, Dambuza IM, Berry SH, Reid DM, McVey SM, Mesiarikova M, John L, Davie M, Baker CP, Arthur JSC, Delibegovic M, Brown GD, Wilson HM. PTP1B deficiency in myeloid cells increases susceptibility to Candida albicans systemic infection by modulating antifungal immunity. mBio 2025 Oct 8;16(10):e0151625.
    doi: 10.1128/mbio.01516-25pubmed: 40879376google scholar: lookup
  2. Katagiri D, Nagasaka S, Takahashi K, Shimizu A, Harris RC, Takahashi T. Protein Tyrosine Phosphatase 1B (PTP1B) Deficiency Substantially Attenuates Glomerular Injury in Endothelial Nitric Oxide Synthase (eNOS)-Deficient Diabetic Mice. Cureus 2025 Jan;17(1):e78207.
    doi: 10.7759/cureus.78207pubmed: 40027018google scholar: lookup
Subscribe to our newsletter
Join 99,265 horse owners like you who receive our email updates on horse health and nutrition.