Exendin-4, aglucagon-like peptide-1 receptor agonist, modulateshepatic fatty acid composition and -Δ5-desaturase index in a murine model of non-alcoholic steatohepatitis

Abstract

Glucagon-like peptide-1 (GLP-1) is involved in the development of non-alcoholic steatohepatitis (NASH), which is characterized by fatty acid imbalance. The aim of this study was to investigate the effects of the GLP-1 receptor (GLP-1R) agonist, exendin-4 (Ex-4), on hepatic fatty acid metabolism and its key enzyme, Δ-5-desaturase, in a murine model of NASH. NASH was induced in db/db mice fed a methionine-choline deficient (MCD) diet. Ex-4 (n=4) or saline [control (CON); n=4] was administered intraperitoneally for 8 weeks. Steatohepatitis activity was evaluated by non-alcoholic fatty liver disease (NAFLD) activity score. Hepatic fatty acid composition and Δ-5-desaturase index were analyzed by gas chromatography. Ex-4 treatment significantly reduced body weight and the NAFLD activity score. Hepatic concentrations of long-chain saturated fatty acids (SFAs) were significantly higher in the Ex-4 group compared to the CON group (23240±955 vs. 31710±8436 μg/g•liver, P<0.05). Ex-4 significantly reduced hepatic n-3 polyunsaturated fatty acid (PUFA)/n-6 PUFA ratio compared to the CON group (13.83±3.15 vs. 8.73±1.95, P<0.05). In addition, the hepatic Δ-5-desaturase index was significantly reduced in the Ex-4 group compared to the CON group (31.1±12.4 vs. 10.5±3.1, P<0.05). In conclusion, the results showed that Ex-4 improved steatohepatitis in a murine model of NASH. Furthermore, Ex-4 altered hepatic long-chain saturated and PUFA composition and reduced the Δ-5-desaturase index. Thus, Ex-4 may improve NASH by regulating hepatic fatty acid metabolism.