Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common complication of type 2 diabetes (T2D). In fact, NAFLD affects up to 70% of diabetic patients and 90-95% of obese individuals. NAFLD can progress to nonalcoholic steatohepatitis (NASH) which can itself lead to cirrhosis and hepatocellular carcinoma. Despite the life-threatening aspects of these hepatic disorders, validated pharmacologic treatments are still lacking. As GLP-1 receptor agonists (GLP-1 RAs) are now widely used in the treatment of T2D, our study aimed to assess their potential beneficial effects on NAFLD/NASH. Wild type C57BL/6 male mice were fed a methionine-choline deficient (MCD) diet to induce the liver manifestations of NASH (steatosis, hepatocyte ballooning, inflammation, fibrosis). After 3 weeks on MCD diet, mice were subcutaneously infused with either liraglutide (16 μg/d) or saline solution for 4 weeks using osmotic minipumps before being euthanazied for analysis. Liver tissues were studied using qPCR and histological stainings and pathological scores were evaluated by a certified pathologist. Liraglutide-infused mice had similar body and liver weights than saline controls. Histological scores revealed a significant decrease in hepatic inflammation in the liraglutide-infused mice compared to controls, despite a similar degree of steatosis. These observations were associated with a significant downexpression of profibrogenic genes (Col1a1, Col1a2, Col3a1, Timp1, Mmp13, Serpine1, Tgfb1) and inflammatory/immune markers (Tnfa, Itgax, Adgre1) in the liver of liraglutide-treated mice. In addition, genes involved in hepatic stellate cells activation (Acta1, Vim) were also downregulated in liraglutide-treated mice. In conclusion, the long-acting GLP-1 RA liraglutide reduces liver inflammation and fibrosis despite no major action on steatosis. These results suggest anti-inflammatory and anti-fibrotic actions of liraglutide that are independent of lipid metabolism. Disclosure S.A. Montandon: None. E. Somm: None. C. De Vito: None. F.R. Jornayvaz: None. Funding Novo Nordisk
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