2. Academic Validation
  3. Resolution of NASH and hepatic fibrosis by the GLP-1R/GcgR dual-agonist Cotadutide via modulating mitochondrial function and lipogenesis

Resolution of NASH and hepatic fibrosis by the GLP-1R/GcgR dual-agonist Cotadutide via modulating mitochondrial function and lipogenesis

  • Nat Metab. 2020 May;2(5):413-431. doi: 10.1038/s42255-020-0209-6.
Michelle L Boland  # 1,  Rhianna C Laker  # 1,  Karly Mather 1,  Arkadiusz Nawrocki 2,  Stephanie Oldham 1,  Brandon B Boland 1,  Hilary Lewis 3,  James Conway 4,  Jacqueline Naylor 5,  Silvia Guionaud 6,  Michael Feigh 7,  Sanne S Veidal 7,  Louise Lantier 8,  Owen P McGuinness 8,  Joseph Grimsby 1,  Cristina M Rondinone 1,  Lutz Jermutus 5,  Martin R Larsen 2,  James L Trevaskis 1 9,  Christopher J Rhodes 10
Affiliations

Affiliations

  • 1 Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
  • 2 Department of Biochemistry and Molecular Biology, PR group, University of Southern Denmark, Odense, Denmark.
  • 3 Research and Early Development, Oncology, AstraZeneca, Cambridge, UK.
  • 4 Translational Sciences, AstraZeneca, Gaithersburg, MD, USA.
  • 5 Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
  • 6 Global Pathology, AstraZeneca, Cambridge, UK.
  • 7 Gubra, Hørsholm, Denmark.
  • 8 Vanderbilt University Mouse Metabolic Phenotyping Center, Nashville, TN, USA.
  • 9 Gilead Sciences, Foster City, CA, USA.
  • 10 Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA. Christopher.Rhodes@astrazeneca.com.
  • # Contributed equally.
PMID: 32478287 DOI: 10.1038/s42255-020-0209-6
Abstract

Non-alcoholic fatty liver disease and steatohepatitis are highly associated with obesity and type 2 diabetes mellitus. Cotadutide, a GLP-1R/GCGR agonist, was shown to reduce blood glycemia, body weight and hepatic steatosis in patients with T2DM. Here, we demonstrate that the effects of Cotadutide to reduce body weight, food intake and improve glucose control are predominantly mediated through the GLP-1 signaling, while, its action on the liver to reduce lipid content, drive glycogen flux and improve mitochondrial turnover and function are directly mediated through Gcg signaling. This was confirmed by the identification of phosphorylation sites on key lipogenic and glucose metabolism Enzymes in liver of mice treated with Cotadutide. Complementary metabolomic and transcriptomic analyses implicated lipogenic, fibrotic and inflammatory pathways, which are consistent with a unique therapeutic contribution of GCGR agonism by Cotadutide in vivo. Significantly, Cotadutide also alleviated fibrosis to a greater extent than Liraglutide or Obeticholic acid (OCA), despite adjusting dose to achieve similar weight loss in 2 preclinical mouse models of NASH. Thus Cotadutide, via direct hepatic (GCGR) and extra-hepatic (GLP-1R) effects, exerts multi-factorial improvement in liver function and is a promising therapeutic option for the treatment of steatohepatitis.

Figures
Products