Exenatide Delays the Progression of Nonalcoholic Fatty Liver Disease in C57BL/6 Mice, Which May Involve Inhibition of the NLRP3 Inflammasome through the Mitophagy Pathway

Abstract

Objective This study is aimed at investigating whether exenatide (Exe) delays the progression of nonalcoholic fatty liver disease (NAFLD) in C57BL/6 mice by targeting the NLRP3 inflammasome through the autophagy/mitophagy pathway. Methods Thirty male C57BL/6 mice were randomly divided into three groups: control group (n = 10), model group (n = 10), and Exe (exenatide) group (n = 10). Mouse models of NAFLD and diabetes were established using a high-fat diet and streptozocin. Results The levels of fasting blood glucose (FBG), total cholesterol (TC), and triglyceride (TG) in the serum were significantly reduced after Exe treatment. The body weight, liver weight/body weight, and number of lipid droplets in the liver significantly decreased in Exe-treated mice. Treatment with Exe markedly reduced the levels of liver lipids, malondialdehyde (MDA), and alanine aminotransferase (ALT) in serum and livers. The number of autophagosomes increased significantly in the Exe group. The expression of LC3A/B-II/I, Beclin-1, Parkin, and BNIP3L increased significantly, whereas NLRP3 and IL-1β proteins were suppressed after Exe treatment. Conclusion We successfully established a mouse model of NAFLD and diabetes. Exe may reduce oxidative stress injury and inhibit the NLRP3 inflammasome by enhancing the autophagy/mitophagy pathway in liver, which has a protective effect on the liver in NAFLD and diabetes in C57BL/6 mice.

Protective Effects of Evogliptin on Steatohepatitis in High-Fat-Fed Mice

“…It means that the decreased hepatic steatosis or reduced inflammation is not associated with decreased mitophagy. The discrepancy between our and previous studies [8,19] may be due to the difference in study period. The study duration of ours (16 weeks) was longer than that of Zheng et al or Shao et al (4 weeks).…”

“…If improved steatohepatitis is related to decreased mitophagy, the results of Zheng et al should have shown similar results [19]. However, after sitagliptin treatment of 4 weeks, hepatic lipid accumulation was ameliorated via activation of autophagy in the study of Zheng et al The results of Shao et al also showed that exenatide for 4 weeks reduced oxidative stress and hepatic accumulation by enhancing the autophagy/mitophagy pathway [8]. It means that the decreased hepatic steatosis or reduced inflammation is not associated with decreased mitophagy.…”

“…Autophagy is generally considered to protect against fatty liver and to degrade damaged cell components in hepatocytes [4]. Exenatide, a glucagon-like peptide 1 analog, delays the progression of NAFLD by promoting autophagy [8]. DPP-4 inhibitors are also shown to induce autophagy, and these lead to beneficial effects such as cardioprotection [18], hepatic insulin resistance, or hepatic steatosis [12].…”

Decrease of Cardiac Parkin Protein in Obese Mice

“…Parkin is upregulated in vascular walls (11) or adipose tissue (12) but decreased in the brain substantia nigra (SN) (13) of obese or diabetic mice. In liver, studies show both an increase (14) or a decrease (15) in Parkin level upon obesity. Contrary to our results, Tong et al observed an increase in cardiac parkin protein during HFD consumption, although their paper did not indicate how many weeks of HFD were performed prior the analysis of Parkin (16).…”

Nonalcoholic Fatty Liver Disease

“…GLP is a peptide derived from the L cells of the lower gastrointestinal tract (the small intestine and proximal colon) and known to enhance insulin secretion from pancreatic β cells and inhibit glucagon release from pancreatic α cells (Campbell and Drucker 2013;Ratziu et al 2015). Whereas the GLP1R agonist exenatide enhanced hepatic steatosis (Tanaka et al 2014), hepatic oxidative stress, and hepatic inflammation (Shao et al 2018) and improved adipose tissue lipolysis in different in vivo models, the application of dulaglutide, lixisenatide, liraglutide, and, recently, semaglutide also shows promising results in terms of improvements in hepatic fat, damage, inflammation, and fibrosis (Armstrong et al 2016;Cusi et al 2018;Ipsen et al 2018;Koutsovasilis et al 2018;Petit et al 2017;Rakipovski et al 2018).…”