본문 바로가기
KERD
논문KCI 등재

Cereblon regulates the production of hepatic fibroblast growth factor 23 in diabetes

2

조회

0

다운로드

0

인용

0

참고문헌

키워드

주제분류화학

초록

Cereblon (CRBN) is an extensively expressed protein involvedin crucial physiological processes. This study reveals CRBN’srole in governing hepatic fibroblast growth factor 23 (FGF23)expression and production via the cyclic adenosine monophosphate(cAMP) pathway in diabetic conditions. The expressionsof hepatic Crbn, Yin Yang 1 (Yy1), and Fgf23 genes weresignificantly increased in diabetic mice and forskolin (FSK)-treated primary hepatocytes, correlating with elevated FGF23production. Overexpression of Crbn and Yy1 increased hepaticFGF23 and cytokines by upregulating YY1 gene expression,which was reduced in Crbn- and Yy1-silenced mice and primaryhepatocytes. Besides, we also found that CRBN-mediatedregulation of hepatic FGF23 involved YY1 recruitment to theFgf23 gene promoters, evidenced by reporter assays, deletionstudies, and mutant analyses. These findings identify CRBNand YY1 as key contributors to gluconeogenic signaling-drivenFGF23 production and inflammation in diabetes, highlightingtheir potential as therapeutic targets for addressing metabolicdisorders like diabetes.

Abstract

Cereblon (CRBN) is an extensively expressed protein involvedin crucial physiological processes. This study reveals CRBN’srole in governing hepatic fibroblast growth factor 23 (FGF23)expression and production via the cyclic adenosine monophosphate(cAMP) pathway in diabetic conditions. The expressionsof hepatic Crbn, Yin Yang 1 (Yy1), and Fgf23 genes weresignificantly increased in diabetic mice and forskolin (FSK)-treated primary hepatocytes, correlating with elevated FGF23production. Overexpression of Crbn and Yy1 increased hepaticFGF23 and cytokines by upregulating YY1 gene expression,which was reduced in Crbn- and Yy1-silenced mice and primaryhepatocytes. Besides, we also found that CRBN-mediatedregulation of hepatic FGF23 involved YY1 recruitment to theFgf23 gene promoters, evidenced by reporter assays, deletionstudies, and mutant analyses. These findings identify CRBNand YY1 as key contributors to gluconeogenic signaling-drivenFGF23 production and inflammation in diabetes, highlightingtheir potential as therapeutic targets for addressing metabolicdisorders like diabetes.

참고문헌 (38)

  1. Higgins JJ, "A mutation in a novel ATP-dependent Lon protease gene in a kindred with mild mental retardation", Neurology, 63, pp.1927~1931 (2004)
  2. Higgins JJ, "Dysregulation of large-conductance Ca2+-activated K+ channel expression in nonsyndromal mental retardation due to a cereblon p. R419X mutation", Neurogenetics, 9, pp.219~223 (2008)
  3. Kim HK, "Cereblon in health and disease", Pflugers Arch, 468, pp.1299~1309 (2016)
  4. Lee KM, "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)
  5. Jo JR, "Gluconeogenic signals regulate hepcidin gene expression via a CRBN-KLF15 axis", BMB Rep, 54, pp.221~226 (2021)
  6. Thakurta A, "Absence of mutations in cereblon(CRBN)and DNA damage-binding protein 1(DDB1)genes and significance for IMiD therapy", Leukemia, 28, pp.1129~1131 (2014)
  7. Dann GP, "Cereblon target validation using a covalent inhibitor of neosubstrate recruitment", Methods Enzymol, 681, pp.155~167 (2023)
  8. Watson ER, "Molecular glue CELMoD compounds are regulators of cereblon conformation", Science, 378, pp.549~553 (2022)
  9. Perwad F, "Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25-hydroxyvitamin D-1alpha-hydroxylase expression in vitro", Am J Physiol Renal Physiol, 293, pp.F1577~1583 (2007)
  10. Gutierrez OM, "Fibroblast growth factor 23 and disordered vitamin D metabolism in chronic kidney disease : updating the trade-off hypothesis", Clin J Am Soc Nephrol, 5, pp.1710~1716 (2010)
  11. Nakatani S, "Fibroblast growth factor 23 as regulator of vitamin D metabolism", Adv Exp Med Biol, 1362, pp.47~54 (2022)
  12. Clinkenbeard EL, "Systemic control of bone homeostasis by FGF23 signaling", Curr Mol Biol Rep, 2, pp.62~71 (2016)
  13. Razzaque MS, "FGF23-mediated regulation of systemic phosphate homeostasis: is Klotho an essential player?", Am J Physiol Renal Physiol, 296, pp.F470~476 (2009)
  14. Shimada T, "Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism", J Clin Invest, 113, pp.561~568 (2004)
  15. Hesse M, "Ablation of vitamin D signaling rescues bone, mineral, and glucose homeostasis in Fgf-23 deficient mice", Matrix Biol, 26, pp.75~84 (2007)
  16. Wojcik M, "The association of FGF23levels in obese adolescents with insulin sensitivity", J Pediatr Endocrinol Metab, 25, pp.687~690 (2012)
  17. Garland JS, "Insulin resistance is associated with fibroblast growth factor-23 in stage 3-5 chronic kidney disease patients", J Diabetes Complications, 28, pp.61~65 (2014)
  18. Hanks LJ, "Associations of fibroblast growth factor-23 with markers of inflammation, insulin resistance and obesity in adults", PLoS One, 10, pp.e0122885~ (2015)
  19. Nakashima A, "Association between resistin and fibroblast growth factor 23 in patients with type 2 diabetes mellitus", Sci Rep, 8, pp.13999~ (2018)
  20. Donate-Correa J, "Pathophysiological implications of imbalances in fibroblast growth factor 23 in the development of diabetes", J Clin Med, 10, pp.2583~ (2021)
  21. Rausch S, "The regulation of FGF23under physiological and pathophysiological conditions", Pflugers Arch, 474, pp.281~292 (2022)
  22. van der Vaart A, "Fibroblast growth factor 23, glucose homeostasis, and incident diabetes : findings of 2cohort studies", J Clin Endocrinol Metab, 108, pp.e971~978 (2023)
  23. Thomas MJ, "Unlocking the mechanisms of transcription factor YY1 : are chromatin modifying enzymes the key?", Gene, 236, pp.197~208 (1999)
  24. Gordon S, "Transcription factor YY1 : structure, function, and therapeutic implications in cancer biology", Oncogene, 25, pp.1125~1142 (2006)
  25. Lee SE, "B-cell translocation gene 2 promotes hepatic hepcidin production via induction of Yin Yang 1", Biochem Biophys Res Commun, 460, pp.996~1001 (2015)
  26. Lu Y, "Yin Yang 1 promotes hepatic gluconeogenesis through upregulation of glucocorticoid receptor", Diabetes, 62, pp.1064~1073 (2013)
  27. Blattler SM, "Yin Yang 1 deficiency in skeletal muscle protects against rapamycin-induced diabetic-like symptoms through activation of insulin", IGF signaling, 2012, pp.15, 505~517
  28. Shi J, "The role of YY1in oncogenesis and its potential as a drug target in cancer therapies", Curr Cancer Drug Targets, 15, pp.145~157 (2015)
  29. Lu Y, "Yin Yang 1 promotes hepatic steatosis through repression of farnesoid X receptor in obese mice", Gut, 63, pp.170~178 (2014)
  30. Lee SE, "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)
  31. Jo JR, "Growth hormone promotes hepatic gluconeogenesis by enhancing BTG2-YY1 signaling pathway", Sci Rep, 11, pp.18999~ (2021)
  32. Marchelek-Mysliwiec M, "Association of FGF19, FGF21 and FGF23 with carbohydrate metabolism parameters and insulin resistance in patients with chronic kidney disease", J Appl Biomed, 18, pp.61~69 (2020)
  33. Nakashima A, "Role and treatment of insulin resistance in patients with chronic kidney disease : a review", Nutrients, 13, pp.4349~ (2021)
  34. Rossaint J, "FGF23signaling impairs neutrophil recruitment and host defense during CKD", J Clin Invest, 126, pp.962~974 (2016)
  35. Nemeth E, "IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin", J Clin Invest, 113, pp.1271~1276 (2004)
  36. Guo YC, "Fibroblast growth factor 23and bone mineralisation", Int J Oral Sci, 7, pp.8~13 (2015)
  37. El-Hodhod MA, "Fibroblast growth factor 23 contributes to diminished bone mineral density in childhood inflammatory bowel disease", BMC Gastroenterol, 12, pp.44~ (2012)
  38. Park S, "Long-term depletion of cereblon induces mitochondrial dysfunction in cancer cells", BMB Rep, 54, pp.305~310 (2021)

관련 논문AI추천

Gluconeogenic signals regulate hepcidin gene expression via a CRBN-KLF15 axis김용득, Balachandar Nedumaran, Jeong-Rang Jo, Keun-Gyu Park, Seungwon An, Sung-Eun Lee, Swati Ghosh생화학분자생물학회 · BMB Reports2021 · 제54권 제4호Enhancement of the SESN2-SHP cascade by melatonin ameliorates hepatic gluconeogenesis by inhibiting the CRBN-BTG2-CREBH signaling pathwayAn Seungwon, Djalilian Ali R., Harris Robert A., Joo Dong Jin, Kim Yong Deuk, Koh Hong, Lee Hyungjo, Nedumaran Balachandar, Park Chul-Seung, Shin Keong Sub생화학분자생물학회 · Experimental and Molecular Medicine2023 · 제55권 Cereblon Deletion Ameliorates Lipopolysaccharide-induced Proinflammatory Cytokines through 5′-Adenosine Monophosphate-Activated Protein Kinase/Heme Oxygenase-1 Activation in ARPE-19 Cells김윤규, 안다은, 양훈지, 여명구, 이경진, 이시온, 채수철대한면역학회 · Immune Network2020 · 제20권 제3호The transcription factor BBX regulates phosphate homeostasis through the modulation of FGF23김정은, 조의식, Bae Yong Chul, Choi Je-Yong, Ihn Hye Jung, Jiang Rulang, Kim Ju Ang, Kwon Tae-Yub, Park Eui Kyun, Shin Hong-In, Su Jeong Lee생화학분자생물학회 · Experimental and Molecular Medicine2024 · 제56권 Long-term depletion of cereblon induces mitochondrial dysfunction in cancer cells김정애, 김정훈, Byoung Chul Park, Hyun Seung Ban, Keeok Haam, Kidae Kim, Seulki Park, Sung Goo Park, Sunhong Kim생화학분자생물학회 · BMB Reports2021 · 제54권 제6호Targeting E3 ubiquitin ligases and their adaptors as a therapeutic strategy for metabolic diseasesGi HyunJoon, Jeong Yelin, Jung Young Hoon, Kim KyeongJin, Kim Young Un, Oh Ah-Reum생화학분자생물학회 · Experimental and Molecular Medicine2023 · 제55권

이 간행물의 다른 논문 (6건)