Identification of Annexina1 as an endogenous regulator of RhoA, and its role in the pathophysiology and experimental therapy of type-2 diabetes

Gareth S.D. Purvis, Massimo Collino, Rodrigo A. Loiola, Andrea Baragetti, Fausto Chiazza, Martina Brovelli, Madeeha H. Sheikh, Debora Collotta, Alessia Cento, Raffaella Mastrocola, Manuela Aragno, Juan C. Cutrin, Chris Reutelingsperger, Liliana Grigore, Alberico L. Catapano, Magdi M. Yaqoob, Giuseppe Danilo Norata, Egle Solito, Christoph Thiemermann

Research output: Contribution to journalArticle

Abstract

Annexin A1 (ANXA1) is an endogenously produced anti-inflammatory protein, which plays an important role in the pathophysiology of diseases associated with chronic inflammation. We demonstrate that patients with type-2 diabetes have increased plasma levels of ANXA1 when compared to normoglycemic subjects. Plasma ANXA1 positively correlated with fatty liver index and elevated plasma cholesterol in patients with type-2 diabetes, suggesting a link between aberrant lipid handling, and ANXA1. Using a murine model of high fat diet (HFD)induced insulin resistance, we then investigated (a) the role of endogenous ANXA1 in the pathophysiology of HFD-induced insulin resistance using ANXA1−/− mice, and (b) the potential use of hrANXA1 as a new therapeutic approach for experimental diabetes and its microvascular complications. We demonstrate that: (1) ANXA1−/− mice fed a HFD have a more severe diabetic phenotype (e.g., more severe dyslipidemia, insulin resistance, hepatosteatosis, and proteinuria) compared to WT mice fed a HFD; (2) treatment of WT-mice fed a HFD with hrANXA1 attenuated the development of insulin resistance, hepatosteatosis and proteinuria. We demonstrate here for the first time that ANXA1−/− mice have constitutively activated RhoA. Interestingly, diabetic mice, which have reduced tissue expression of ANXA1, also have activated RhoA. Treatment of HFD-mice with hrANXA1 restored tissue levels of ANXA1 and inhibited RhoA activity, which, in turn, resulted in restoration of the activities of Akt, GSK-3β and endothelial nitric oxide synthase (eNOS) secondary to re-sensitization of IRS-1 signaling. We further demonstrate in human hepatocytes that ANXA1 protects against excessive mitochondrial proton leak by activating FPR2 under hyperglycaemic conditions. In summary, our data suggest that (a) ANXA1 is a key regulator of RhoA activity, which restores IRS-1 signal transduction and (b) recombinant human ANXA1 may represent a novel candidate for the treatment of T2D and/or its complications.

Original languageEnglish
Article number571
JournalFrontiers in Immunology
Volume10
Issue numberMAR
DOIs
Publication statusPublished - Jan 1 2019

Keywords

  • Annexin A1
  • Hepatosteatosis
  • Metabolism
  • Nephropathy
  • Rho A
  • Type-2 diabetes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Purvis, G. S. D., Collino, M., Loiola, R. A., Baragetti, A., Chiazza, F., Brovelli, M., Sheikh, M. H., Collotta, D., Cento, A., Mastrocola, R., Aragno, M., Cutrin, J. C., Reutelingsperger, C., Grigore, L., Catapano, A. L., Yaqoob, M. M., Norata, G. D., Solito, E., & Thiemermann, C. (2019). Identification of Annexina1 as an endogenous regulator of RhoA, and its role in the pathophysiology and experimental therapy of type-2 diabetes. Frontiers in Immunology, 10(MAR), [571]. https://doi.org/10.3389/fimmu.2019.00571