Abstract
Background/AimsExenatide is a glucagon-like polypeptide-1 analog, whose main clinical use is to treat type 2 diabetes. However, the mechanism of exenatide in mitigating non-alcoholic steatohepatitis (NASH) remains unclear. This study aimed to investigate the in vitro and in vivo effect of exenatide on NASH.MethodsLeptin receptor-deficient C57BL/KsJ- db/db male mice were fed with methionine-choline-deficient (MCD) diet for 4 weeks to induce NASH, while oleic acid/LPS-treated HepG2 cells were used as an in vitro cell model. Exenatide (20 µg/kg/day, subcutaneous) and specific exenatide inhibitors (20 µg/kg/day, intraperitoneal) were used to determine the effects of exenatide on NASH.ResultsExenatide treatment inhibited the pyroptosis signaling pathway to attenuate NASH.ConclusionTo the best of our knowledge, this report provides the first evidence showing that exenatide attenuated NASH by inhibiting the pyroptosis signaling pathway. Exenatide thus has important pathophysiological functions in NASH and may represent a useful new therapeutic target.
Highlights
Exenatide is a glucagon-like polypeptide-1 (GLP-1) analog initially discovered in saliva of the American tailed poisonous lizard
The results indicated that exenatide attenuated oleic acid-induced non-alcoholic steatohepatitis (NASH) (Figure 1A)
gasdermin D (GSDMD) protein expression levels were increased by oleic acid, and this increase was significantly inhibited by exenatide, as demonstrated by western blotting (Figure 1B)
Summary
Exenatide is a glucagon-like polypeptide-1 (GLP-1) analog initially discovered in saliva of the American tailed poisonous lizard. The molecular structure of exenatide is homologous to GLP-1, and it binds to GLP-1 receptors in humans and acts like GLP-1. The use of exenatide for the treatment of type 2 diabetes has a cardiovascular protective effect, by reducing systolic blood pressure and the incidences of heart failure, myocardial ischemia, and myocardial infarction [4, 5]. The role of exenatide in the Abbreviations: GSDMD, gasdermin D; NASH, non-alcoholic steatohepatitis; NAFLD, non-alcoholic fatty liver disease; NLRP3, nucleotide-binding oligomerization domain-like receptor protein 3; GLP-1, glucagon-like polypeptide-1. Exenatide Attenuated Non-Alcoholic Steatohepatitis clinical treatment of non-alcoholic steatohepatitis (NASH) is unclear, and further studies are needed to provide a theoretical basis for the clinical application
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