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

Autor: Boland ML; Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA., Laker RC; Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA., Mather K; Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA., Nawrocki A; Department of Biochemistry and Molecular Biology, PR group, University of Southern Denmark, Odense, Denmark., Oldham S; Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA., Boland BB; Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA., Lewis H; Research and Early Development, Oncology, AstraZeneca, Cambridge, UK., Conway J; Translational Sciences, AstraZeneca, Gaithersburg, MD, USA., Naylor J; Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Guionaud S; Global Pathology, AstraZeneca, Cambridge, UK., Feigh M; Gubra, Hørsholm, Denmark., Veidal SS; Gubra, Hørsholm, Denmark., Lantier L; Vanderbilt University Mouse Metabolic Phenotyping Center, Nashville, TN, USA., McGuinness OP; Vanderbilt University Mouse Metabolic Phenotyping Center, Nashville, TN, USA., Grimsby J; Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA., Rondinone CM; Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA., Jermutus L; Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Larsen MR; Department of Biochemistry and Molecular Biology, PR group, University of Southern Denmark, Odense, Denmark., Trevaskis JL; Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.; Gilead Sciences, Foster City, CA, USA., Rhodes CJ; Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA. Christopher.Rhodes@astrazeneca.com.
Jazyk: angličtina
Zdroj: Nature metabolism [Nat Metab] 2020 May; Vol. 2 (5), pp. 413-431. Date of Electronic Publication: 2020 May 21.
DOI: 10.1038/s42255-020-0209-6
Abstrakt: 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.
Competing Interests: COMPETING INTERESTS STATEMENT The authors declare competing interests as defined by Nature Research. Employee of AstraZeneca (R.C.L., K.M., S.O., J.C., J.N., J.G., L.J., C.J.R.). Owns stock in AstraZeneca (K.M., S.O., J.C., J.N., J.G., L.J., C.M.R., J.L.T., C.J.R.).
Databáze: MEDLINE
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