Pathophysiological significance of hepatokine overproduction in type 2 diabetes
- 159 Downloads
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.
KeywordsHepatokines Selenoprotein P LECT2 Insulin resistance
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.
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).
All institutional and national guidelines for the care and use of laboratory animals were followed.
- 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
- 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
- 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