Advertisement

Diabetology International

, Volume 9, Issue 4, pp 224–233 | Cite as

Pathophysiological significance of hepatokine overproduction in type 2 diabetes

  • Hirofumi Misu
Review Article
  • 78 Downloads

Abstract

Currently, many studies draw attention to novel secretory factors, such as adipokines or myokines, derived from the tissues that were not originally recognized as endocrine organs. The liver may contribute to the onset of various kinds of pathologies of type 2 diabetes by way of the production of secretory proteins “hepatokines.” Using the comprehensive gene expression analyses in human livers, we have rediscovered selenoprotein P and LECT2 as hepatokines involved in the onset of dysregulated glucose metabolism. Overproduction of selenoprotein P, previously reported as a transport protein of selenium, induces insulin resistance and hyperglycemia in type 2 diabetic condition. Selenoprotein P also contributes to vascular complications of type 2 diabetes directly by inducing VEGF resistance in vascular endothelial cells. Notably, selenoprotein P impairs health-promoting effects of exercise by inhibiting ROS/AMPK/PGC-1α pathway in the skeletal muscle through its receptor LRP1. Overproduction of LECT2, previously reported as a neutrophil chemotactic protein, links obesity to insulin resistance in the skeletal muscle. Further studies would develop novel diagnostic or therapeutic procedures targeting hepatokines to combat over-nutrition-related diseases such as type 2 diabetes.

Keywords

Hepatokines Selenoprotein P LECT2 Insulin resistance 

Notes

Acknowledgements

Parts of this review were presented by the author as the Lilly Award Lecture at the 61th Annual Meeting of the Japan Diabetes Society, Tokyo, Japan. The author sincerely thanks Profs. Toshinari Takamura and Shuichi Kaneko (Kanazawa University) for their support and mentoring, and also colleagues in the Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences for their support. The author would also like to thank Dr. Masato Kasuga (PRESTO, Japan Science and Technology Agency) for his support and helpful advice.

Funding

This work was supported by the following grants: JSPS KAKENHI Grant Numbers 23791022, 25461334, and 16K09740; the Mochida Memorial Foundation for Medical and Pharmaceutical Research; the Takeda Science Foundation; JST Adaptable and Seamless Technology transfer Program (A-STEP) Grant Numbers AS2311400F and 15im0302407.

Compliance with ethical standards

Conflict of interest

Hirofumi Misu received research grant from Eli Lilly, Takeda Pharmaceutical Company, Novartis International AG, and Merck & Co., Inc.

Human rights statement and informed consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Informed consent or substitute for it was obtained from all patients for being included in the study. All experimental protocols were approved by the Ethics Committees of Kanazawa University (Approval no. 2009-067, December 1 2009, Approval no. 2011-049, October 12 2011, and Approval no. 2014-002, September 30 2014).

Animal studies

All institutional and national guidelines for the care and use of laboratory animals were followed.

References

  1. 1.
    Misu H, Takamura T, Matsuzawa N, et al. Genes involved in oxidative phosphorylation are coordinately upregulated with fasting hyperglycaemia in livers of patients with type 2 diabetes. Diabetologia. 2007;2:268–77.CrossRefGoogle Scholar
  2. 2.
    Misu H, Takamura T, Takayama H, et al. A liver-derived secretory protein, selenoprotein P, causes insulin resistance. Cell Metab. 2010;5:483–95.CrossRefGoogle Scholar
  3. 3.
    Burk RF, Hill KE. Selenoprotein P-expression, functions, and roles in mammals. Biochem Biophys Acta. 2009;11:1441–7.CrossRefGoogle Scholar
  4. 4.
    Saito Y, Takahashi K. Characterization of selenoprotein P as a selenium supply protein. Eur J Biochem. 2002;22:5746–51.CrossRefGoogle Scholar
  5. 5.
    Arteel GE, Mostert V, Oubrahim H, et al. Protection by selenoprotein P in human plasma against peroxynitrite-mediated oxidation and nitration. Biol Chem. 1998;8–9:1201–5.Google Scholar
  6. 6.
    Hill KE, Zhou J, McMahan WJ, et al. Deletion of selenoprotein P alters distribution of selenium in the mouse. J Biol Chem. 2003;16:13640–6.CrossRefGoogle Scholar
  7. 7.
    Schomburg L, Schweizer U, Holtmann B, et al. Gene disruption discloses role of selenoprotein P in selenium delivery to target tissues. Biochem J. 2003;370(Pt 2):397–402.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Ruderman NB, Carling D, Prentki M, et al. AMPK, insulin resistance, and the metabolic syndrome. J Clin Invest. 2013;7:2764–72.CrossRefGoogle Scholar
  9. 9.
    Takayama H, Misu H, Iwama H, et al. Metformin suppresses expression of the selenoprotein P gene via an AMP-activated kinase (AMPK)/FoxO3a pathway in H4IIEC3 hepatocytes. J Biol Chem. 2014;1:335–45.CrossRefGoogle Scholar
  10. 10.
    Simons M. Angiogenesis, arteriogenesis, and diabetes: paradigm reassessed? J Am Coll Cardiol. 2005;5:835–7.CrossRefGoogle Scholar
  11. 11.
    Abaci A, Oguzhan A, Kahraman S, et al. Effect of diabetes mellitus on formation of coronary collateral vessels. Circulation. 1999;17:2239–42.CrossRefGoogle Scholar
  12. 12.
    Yarom R, Zirkin H, Stammler G, et al. Human coronary microvessels in diabetes and ischaemia. Morphometric study of autopsy material. J Pathol. 1992;3:265–70.CrossRefGoogle Scholar
  13. 13.
    Al-Delaimy WK, Merchant AT, Rimm EB, et al. Effect of type 2 diabetes and its duration on the risk of peripheral arterial disease among men. Am J Med. 2004;4:236–40.CrossRefGoogle Scholar
  14. 14.
    Hueb W, Gersh BJ, Costa F, et al. Impact of diabetes on five-year outcomes of patients with multivessel coronary artery disease. Ann Thorac Surg. 2007;1:93–9.CrossRefGoogle Scholar
  15. 15.
    Galiano RD, Tepper OM, Pelo CR, et al. Topical vascular endothelial growth factor accelerates diabetic wound healing through increased angiogenesis and by mobilizing and recruiting bone marrow-derived cells. Am J Pathol. 2004;6:1935–47.CrossRefGoogle Scholar
  16. 16.
    Boodhwani M, Sellke FW. Therapeutic angiogenesis in diabetes and hypercholesterolemia: influence of oxidative stress. Antioxid Redox Signal. 2009;8:1945–59.CrossRefGoogle Scholar
  17. 17.
    Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes—a review. Diabet Med. 2010;1:4–14.CrossRefGoogle Scholar
  18. 18.
    Waltenberger J. VEGF resistance as a molecular basis to explain the angiogenesis paradox in diabetes mellitus. Biochem Soc Trans. 2009;37(Pt 6):1167–70.CrossRefPubMedGoogle Scholar
  19. 19.
    Arteel GE, Franken S, Kappler J, et al. Binding of selenoprotein P to heparin: characterization with surface plasmon resonance. Biol Chem. 2000;3:265–8.Google Scholar
  20. 20.
    Burk RF, Hill KE, Boeglin ME, et al. Selenoprotein P associates with endothelial cells in rat tissues. Histochem Cell Biol. 1997;1:11–5.CrossRefGoogle Scholar
  21. 21.
    Ushio-Fukai M. VEGF signaling through NADPH oxidase-derived ROS. Antioxid Redox Signal. 2007;6:731–9.CrossRefGoogle Scholar
  22. 22.
    Ishikura K, Misu H, Kumazaki M, et al. Selenoprotein P as a diabetes-associated hepatokine that impairs angiogenesis by inducing VEGF resistance in vascular endothelial cells. Diabetologia. 2014;9:1968–76.CrossRefGoogle Scholar
  23. 23.
    Bishop-Bailey D. Mechanisms governing the health and performance benefits of exercise. Br J Pharmacol. 2013;6:1153–66.CrossRefGoogle Scholar
  24. 24.
    Bouchard C, An P, Rice T, et al. Familial aggregation of VO2max response to exercise training: results from the HERITAGE Family Study. J Appl Physiol. 1999;3:1003–8.CrossRefGoogle Scholar
  25. 25.
    Stephens NA, Sparks LM. Resistance to the beneficial effects of exercise in type 2 diabetes: are some individuals programmed to fail? J Clin Endocrinol Metab. 2014.  https://doi.org/10.1210/jc.2014-2545.CrossRefPubMedGoogle Scholar
  26. 26.
    Niess AM, Simon P. Response and adaptation of skeletal muscle to exercise–the role of reactive oxygen species. Front Biosci. 2007;12:4826–38.CrossRefPubMedGoogle Scholar
  27. 27.
    Handschin C, Spiegelman BM. The role of exercise and PGC1alpha in inflammation and chronic disease. Nature. 2008;7203:463–9.CrossRefGoogle Scholar
  28. 28.
    Narkar VA, Downes M, Yu RT, et al. AMPK and PPARdelta agonists are exercise mimetics. Cell. 2008;3:405–15.CrossRefGoogle Scholar
  29. 29.
    Cardaci S, Filomeni G, Ciriolo MR. Redox implications of AMPK-mediated signal transduction beyond energetic clues. J Cell Sci. 2012;125(Pt 9):2115–25.CrossRefPubMedGoogle Scholar
  30. 30.
    Kang C, O’Moore KM, Dickman JR, et al. Exercise activation of muscle peroxisome proliferator-activated receptor-gamma coactivator-1alpha signaling is redox sensitive. Free Radic Biol Med. 2009;10:1394–400.CrossRefGoogle Scholar
  31. 31.
    Ristow M, Zarse K, Oberbach A, et al. Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci USA. 2009;21:8665–70.CrossRefGoogle Scholar
  32. 32.
    Gomez-Cabrera MC, Domenech E, Romagnoli M, et al. Oral administration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance. Am J Clin Nutr. 2008;1:142–9.CrossRefGoogle Scholar
  33. 33.
    Misu H, Takayama H, Saito Y, et al. Deficiency of the hepatokine selenoprotein P increases responsiveness to exercise in mice through upregulation of reactive oxygen species and AMP-activated protein kinase in muscle. Nat Med. 2017;4:508–16.CrossRefGoogle Scholar
  34. 34.
    Olson GE, Winfrey VP, Nagdas SK, et al. Apolipoprotein E receptor-2 (ApoER2) mediates selenium uptake from selenoprotein P by the mouse testis. J Biol Chem. 2007;16:12290–7.CrossRefGoogle Scholar
  35. 35.
    Olson GE, Winfrey VP, Hill KE, et al. Megalin mediates selenoprotein P uptake by kidney proximal tubule epithelial cells. J Biol Chem. 2008;11:6854–60.CrossRefGoogle Scholar
  36. 36.
    Takamura T, Misu H, Ota T, et al. Fatty liver as a consequence and cause of insulin resistance: lessons from type 2 diabetic liver. Endocr J. 2012;9:745–63.CrossRefGoogle Scholar
  37. 37.
    Hsieh PS, Hsieh YJ. Impact of liver diseases on the development of type 2 diabetes mellitus. World J Gastroenterol. 2011;48:5240–5.CrossRefGoogle Scholar
  38. 38.
    Kotronen A, Seppala-Lindroos A, Bergholm R, et al. Tissue specificity of insulin resistance in humans: fat in the liver rather than muscle is associated with features of the metabolic syndrome. Diabetologia. 2008;1:130–8.Google Scholar
  39. 39.
    Fabbrini E, Magkos F, Mohammed BS, et al. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci USA. 2009;36:15430–5.CrossRefGoogle Scholar
  40. 40.
    D’Adamo E, Cali AM, Weiss R, et al. Central role of fatty liver in the pathogenesis of insulin resistance in obese adolescents. Diabetes Care. 2010;8:1817–22.CrossRefGoogle Scholar
  41. 41.
    Lan F, Misu H, Chikamoto K, et al. LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance. Diabetes. 2014;5:1649–64.CrossRefGoogle Scholar
  42. 42.
    Yamagoe S, Yamakawa Y, Matsuo Y, et al. Purification and primary amino acid sequence of a novel neutrophil chemotactic factor LECT2. Immunol Lett. 1996;1:9–13.CrossRefGoogle Scholar
  43. 43.
    Yamagoe S, Mizuno S, Suzuki K. Molecular cloning of human and bovine LECT2 having a neutrophil chemotactic activity and its specific expression in the liver. Biochim Biophys Acta. 1998;1:105–13.CrossRefGoogle Scholar
  44. 44.
    Saito T, Okumura A, Watanabe H, et al. Increase in hepatic NKT cells in leukocyte cell-derived chemotaxin 2-deficient mice contributes to severe concanavalin A-induced hepatitis. J Immunol. 2004;1:579–85.CrossRefGoogle Scholar
  45. 45.
    Anson M, Crain-Denoyelle AM, Baud V, et al. Oncogenic beta-catenin triggers an inflammatory response that determines the aggressiveness of hepatocellular carcinoma in mice. J Clin Invest. 2012;2:586–99.CrossRefGoogle Scholar
  46. 46.
    Viollet B, Guigas B, Leclerc J, et al. AMP-activated protein kinase in the regulation of hepatic energy metabolism: from physiology to therapeutic perspectives. Acta Physiol. 2009;1:81–98.CrossRefGoogle Scholar
  47. 47.
    Alter J, Rozentzweig D, Bengal E. Inhibition of myoblast differentiation by tumor necrosis factor alpha is mediated by c-Jun N-terminal kinase 1 and leukemia inhibitory factor. J Biol Chem. 2008;34:23224–34.CrossRefGoogle Scholar
  48. 48.
    Stefan N, Haring HU. The role of hepatokines in metabolism. Nat Rev Endocrinol. 2013;3:144–52.CrossRefGoogle Scholar
  49. 49.
    Meex RCR, Watt MJ. Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance. Nat Rev Endocrinol. 2017;9:509–20.CrossRefGoogle Scholar
  50. 50.
    Mita Y, Nakayama K, Inari S, et al. Selenoprotein P-neutralizing antibodies improve insulin secretion and glucose sensitivity in type 2 diabetes mouse models. Nat Commun. 2017;1:1658.CrossRefGoogle Scholar
  51. 51.
    Tanaka M, Saito Y, Misu H, et al. Development of a sol particle homogeneous immunoassay for measuring full-length selenoprotein P in human serum. J Clin Lab Anal. 2016;2:114–22.CrossRefGoogle Scholar

Copyright information

© The Japan Diabetes Society 2018

Authors and Affiliations

  1. 1.Department of Endocrinology and MetabolismKanazawa University Graduate School of Medical SciencesKanazawaJapan
  2. 2.PRESTO, Japan Science and Technology AgencyKawaguchiJapan

Personalised recommendations