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Resolution of NASH and hepatic fibrosis by the GLP-1R/GcgR dual-agonist
Cotadutide via modulating mitochondrial function and lipogenesis.
Authors Boland ML, Laker RC, Mather K, Nawrocki A, Oldham S, Boland BB, Lewis H, Conway
J, Naylor J, Guionaud S, Feigh M, Veidal SS, Lantier L, McGuinness OP, Grimsby
J, Rondinone CM, Jermutus L, Larsen MR, Trevaskis JL, Rhodes CJ
Submitted By Submitted Externally on 9/28/2020
Status Published
Journal Nature metabolism
Year 2020
Date Published 5/1/2020
Volume : Pages 2 : 413 - 431
PubMed Reference 32478287
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.


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