Enhancement of the SESN2-SHP cascade by melatonin ameliorates hepatic gluconeogenesis by inhibiting the CRBN-BTG2-CREBH signaling pathway
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Melatonin is involved in the regulation of various biological functions. Here, we explored a novel molecular mechanism by which the melatonin-induced sestrin2 (SESN2)-small heterodimer partner (SHP) signaling pathway protects against fasting- and diabetes-mediated hepatic glucose metabolism. Various key gene expression analyses were performed and multiple metabolic changes were assessed in liver specimens and primary hepatocytes of mice and human participants. The expression of the hepatic cereblon (CRBN) and b-cell translocation gene 2 (BTG2) genes was significantly increased in fasting mice, diabetic mice, and patients with diabetes. Overexpression of Crbn and Btg2 increased hepatic gluconeogenesis by enhancing cyclic adenosine monophosphate (cAMP)-responsive element-binding protein H (CREBH), whereas this phenomenon was prominently ablated in Crbn null mice and Btg2-silenced mice. Interestingly, melatonin-induced SESN2 and SHP markedly reduced hepatic glucose metabolism in diabetic mice and primary hepatocytes, and this protective effect of melatonin was strikingly reversed by silencing Sesn2 and Shp. Finally, the melatonin-induced SESN2-SHP signaling pathway inhibited CRBN- and BTG2-mediated hepatic gluconeogenic gene transcription via the competition of BTG2 and the interaction of CREBH. Mitigation of the CRBN-BTG2-CREBH axis by the melatonin-SESN2-SHP signaling network may provide a novel therapeutic strategy to treat metabolic dysfunction due to diabetes.
Abstract
Melatonin is involved in the regulation of various biological functions. Here, we explored a novel molecular mechanism by which the melatonin-induced sestrin2 (SESN2)-small heterodimer partner (SHP) signaling pathway protects against fasting- and diabetes-mediated hepatic glucose metabolism. Various key gene expression analyses were performed and multiple metabolic changes were assessed in liver specimens and primary hepatocytes of mice and human participants. The expression of the hepatic cereblon (CRBN) and b-cell translocation gene 2 (BTG2) genes was significantly increased in fasting mice, diabetic mice, and patients with diabetes. Overexpression of Crbn and Btg2 increased hepatic gluconeogenesis by enhancing cyclic adenosine monophosphate (cAMP)-responsive element-binding protein H (CREBH), whereas this phenomenon was prominently ablated in Crbn null mice and Btg2-silenced mice. Interestingly, melatonin-induced SESN2 and SHP markedly reduced hepatic glucose metabolism in diabetic mice and primary hepatocytes, and this protective effect of melatonin was strikingly reversed by silencing Sesn2 and Shp. Finally, the melatonin-induced SESN2-SHP signaling pathway inhibited CRBN- and BTG2-mediated hepatic gluconeogenic gene transcription via the competition of BTG2 and the interaction of CREBH. Mitigation of the CRBN-BTG2-CREBH axis by the melatonin-SESN2-SHP signaling network may provide a novel therapeutic strategy to treat metabolic dysfunction due to diabetes.
참고문헌 (35)
- Tricoire, H., "Melatonin enters the cerebrospinal fluid through the pineal recess", Endocrinology, 143, pp.84~90 (2002)
- Tarocco, A., "Melatonin as a master regulator of cell death and inflammation : molecular mechanisms and clinical implications for newborn care", Cell Death Dis, 10, pp.317~ (2019)
- Liu, W., "Melatonin Alleviates Glucose and Lipid Metabolism Disorders in Guinea Pigs Caused by Different Artificial Light Rhythms", J. Diabetes Res, 2020, pp.4927403~ (2020)
- Cecon, E., "Melatonin receptors : molecular pharmacology and signalling in the context of system bias", Br. J. Pharm, 175, pp.3263~3280 (2018)
- Majidinia, M., "The role of melatonin, a multitasking molecule, in retarding the processes of ageing", Ageing Res Rev, 47, pp.198~213 (2018)
- Ma, H., "ROR : Nuclear Receptor for Melatonin or Not?", Molecules, 26, pp.2693~ (2021)
- Hardeland, R., "Melatonin and inflammation-Story of a double-edged blade", J. Pineal Res, 65, pp.e12525~ (2018)
- Su, S. C, "Functional Interaction between Melatonin Signaling and Noncoding RNAs", Trends Endocrinol. Metab, 29, pp.435~445 (2018)
- Faria, J. A., "Melatonin acts through MT1", MT2 receptors to activate hypothalamic Akt and suppress hepatic gluconeogenesis in rats, 2013, pp.305, E230~E242
- Chen, J., "Protective effects of melatonin on sepsis-induced liver injury and dysregulation of gluconeogenesis in rats through activating SIRT1", STAT3 pathway, 2019, pp.117, 109150~
- Nogueira, T. C., "Absence of melatonin induces night-time hepatic insulin resistance and increased gluconeogenesis due to stimulation of nocturnal unfolded protein response", Endocrinology, 152, pp.1253~1263 (2011)
- Shin, H. J., "Multiomic Analysis of Cereblon Expression and Its Prognostic Value in Kidney Renal Clear Cell Carcinoma, Lung Adenocarcinoma, and Skin Cutaneous Melanoma", J. Pers. Med, 11, pp.263~ (2021)
- Kim, H. K., "Cereblon in health and disease", Pflug. Arch, 468, pp.1299~1309 (2016)
- Lee, K. M., "Functional effects of a pathogenic mutation in Cereblon(CRBN)on the regulation of protein synthesis via the AMPK-mTOR cascade", J. Biol. Chem, 289, pp.23343~23352 (2014)
- Lee, K. M., "Disruption of the cereblon gene enhances hepatic AMPK activity and prevents high-fat diet-induced obesity and insulin resistance in mice", Diabetes, 62, pp.1855~1864 (2013)
- Melamed, J., "Expression of B-cell translocation gene 2protein in normal human tissues", Tissue Cell, 34, pp.28~32 (2002)
- Seung-Lark Hwang, "B-cell translocation gene 2 positively regulates GLP-1-stimulated insulin secretion via induction of PDX-1 in pancreatic b-cells", Experimental and Molecular Medicine, 45(5), pp.1~7 (2013), 생화학분자생물학회
- Hwang, S. L., "B-cell translocation gene-2 increases hepatic gluconeogenesis via induction of CREB", Biochem Biophys. Res Commun, 427, pp.801~805 (2012)
- Kim, Y. D., "B-cell translocation gene 2 regulates hepatic glucose homeostasis via induction of orphan nuclear receptor Nur77 in diabetic mouse model", Diabetes, 63, pp.1870~1880 (2014)
- Wang, M., "bZIP transmembrane transcription factor CREBH : Potential role in non-alcoholic fatty liver disease(Review)", Mol. Med Rep, 13, pp.1455~1462 (2016)
- Nakagawa, Y., "CREBH Regulates Systemic Glucose and Lipid Metabolism", Int J. Mol. Sci, 19, pp.1396~ (2018)
- Wang, L. X., "Sestrin2 : Its Potential Role and Regulatory Mechanism in Host Immune Response in Diseases", Front Immunol, 10, pp.2797~ (2019)
- Hwang, H. J., "Knockdown of Sestrin2 Increases Lipopolysaccharide-Induced Oxidative Stress, Apoptosis, and Fibrotic Reactions in H9c2 Cells and Heart Tissues of Mice via an AMPK-Dependent Mechanism", Mediators Inflamm, 2018, pp.6209140~ (2018)
- Chanda, D., "Molecular basis of endocrine regulation by orphan nuclear receptor Small Heterodimer Partner", Endocr. J, 55, pp.253~268 (2008)
- Wu, J., "The long and the small collide : LncRNAs and small heterodimer partner(SHP)in liver disease", Mol. Cell Endocrinol, 528, pp.111262~ (2021)
- Kim, D. K., "Inverse agonist of nuclear receptor ERRγ mediates antidiabetic effect through inhibition of hepatic gluconeogenesis", Diabetes, 62, pp.3093~3102 (2013)
- Lee, M. W., "Regulation of hepatic gluconeogenesis by an ER-bound transcription factor, CREBH", Cell Metab, 11, pp.331~339 (2010)
- Kim, Y. D., "Metformin inhibits growth hormone-mediated hepatic PDK4 gene expression through induction of orphan nuclear receptor small heterodimer partner", Diabetes, 61, pp.2484~2494 (2012)
- Lee, S. E., "Induction of SIRT1 by melatonin improves alcohol-mediated oxidative liver injury by disrupting the CRBN-YY1-CYP2E1 signaling pathway", J. Pineal Res, 68, pp.e12638~ (2020)
- Byun, J. K., "A Positive Feedback Loop between Sestrin2 and mTORC2 Is Required for the Survival of Glutamine-Depleted Lung Cancer Cells", Cell Rep, 20, pp.586~599 (2017)
- Lee, K. M., "Functional modulation of AMPactivated protein kinase by cereblon", Biochim Biophys. Acta, 1813, pp.448~455 (2011)
- Kim, H., "CREBH Maintains Circadian Glucose Homeostasis by Regulating Hepatic Glycogenolysis and Gluconeogenesis", Mol. Cell Biol, 37, pp.e00048~ (2017)
- Kim, Y. D., "Metformin inhibits hepatic gluconeogenesis through AMPactivated protein kinase-dependent regulation of the orphan nuclear receptor SHP", Diabetes, 57, pp.306~314 (2008)
- Lee, J. M., "AMPK-dependent repression of hepatic gluconeogenesis via disruption of CREB.CRTC2 complex by orphan nuclear receptor small heterodimer partner", J. Biol. Chem, 285, pp.32182~32191 (2010)
- Kim, Y. D., "Orphan nuclear receptor small heterodimer partner negatively regulates growth hormone-mediated induction of hepatic gluconeogenesis through inhibition of signal transducer and activator of transcription 5(STAT5)transactivation", J. Biol. Chem, 287, pp.37098~37108 (2012)