Author:
Khalifa Olfa,AL-Akl Neyla S.,Errafii Khaoula,Arredouani Abdelilah
Abstract
AbstractNon-alcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide. Agonists of the glucagon-like peptide-1 receptor (GLP-1R), currently approved to treat type 2 diabetes, hold promise to improve steatosis and even steatohepatitis. However, due to their pleiotropic effects, the mechanisms underlying their protective effect on NAFLD remain elusive. We aimed to investigate these mechanisms using an in vitro model of steatosis treated with the GLP-1R agonist Exendin-4 (Ex-4). We established steatotic HepG2 cells by incubating the cells with 400 µM oleic acid (OA) overnight. Further treatment with 200 nM Ex-4 for 3 h significantly reduced the OA-induced lipid accumulation (p < 0.05). Concomitantly, Ex-4 substantially reduced the expression levels of Fatty Acid-Binding Protein 1 (FABP1) and its primary activator, Forkhead box protein A1 (FOXA1). Interestingly, the silencing of β-catenin with siRNA abolished the effect of Ex-4 on these genes, suggesting dependency on the Wnt/β-catenin pathway. Additionally, after β-catenin silencing, OA treatment significantly increased the expression of nuclear transcription factors SREBP-1 and TCF4, whereas Ex-4 significantly decreased this upregulation. Our findings suggest that direct activation of GLP-1R by Ex-4 reduces OA-induced steatosis in HepG2 cells by reducing fatty acid uptake and transport via FABP1 downregulation.
Funder
Open access funding provided by the Qatar National Library
Publisher
Springer Science and Business Media LLC
Reference74 articles.
1. Younossi, Z. M. Non-alcoholic fatty liver disease—A global public health perspective. J. Hepatol. 70(3), 531–544 (2019).
2. Haldar, D. et al. Outcomes of liver transplantation for non-alcoholic steatohepatitis: A european liver transplant registry study. J. Hepatol. 71(2), 313–322 (2019).
3. Cotter, T. G. & Rinella, M. Nonalcoholic fatty liver disease 2020: The state of the disease. Gastroenterology 158(7), 1851–1864 (2020).
4. Perumpail, B. J. et al. Clinical epidemiology and disease burden of nonalcoholic fatty liver disease. World J. Gastroenterol. 23(47), 8263–8276 (2017).
5. Glass, L. M., Hunt, C. M., Fuchs, M. & Su, G. L. Comorbidities and nonalcoholic fatty liver disease: The chicken, the egg, or both?. Fed. Pract. 36(2), 64–71 (2019).
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