Glucagon-like peptide-1 analogue prevents nonalcoholic steatohepatitis in non-obese mice

• Published in: World journal of gastroenterology : WJG 2016-02, Vol.22 (8), p.2512-2523
• Main Authors: Yamamoto, Takaya, Nakade, Yukiomi, Yamauchi, Taeko, Kobayashi, Yuji, Ishii, Norimitsu, Ohashi, Tomohiko, Ito, Kiyoaki, Sato, Ken, Fukuzawa, Yoshitaka, Yoneda, Masashi
• Format: Article
• Language: English
• Subjects: acid; Oxidative; Acyl-CoA Oxidase - genetics; Acyl-CoA Oxidase - metabolism; Animals; Basic Study; Biomarkers - metabolism; cells; Free; Disease Models, Animal; fatty; Fatty Acid Transport Proteins - genetics; Fatty Acid Transport Proteins - metabolism; Fatty Acids, Nonesterified - metabolism; Gene Expression Regulation; Glucagon; Glucagon-Like Peptide 1 - analogs & derivatives; Glucagon-Like Peptide 1 - pharmacology; Inflammation Mediators - metabolism; like; Liver - drug effects; Liver - metabolism; Liver - pathology; Macrophages - drug effects; Macrophages - metabolism; Male; Mice, Inbred NOD; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Non-alcoholic Fatty Liver Disease - prevention & control; Oxidative Stress - drug effects; peptide-1; Nonalcoholic; Peptides - pharmacology; steatohepatitis; Kupffer; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 1 - metabolism; stress; Time Factors; Triglycerides - metabolism; Venoms - pharmacology
• ISSN: 1007-9327; 2219-2840
• DOI: 10.3748/wjg.v22.i8.2512

AIM: To investigate whether a glucagon-like peptide-1(GLP-1) analogue inhibits nonalcoholic steatohepatitis(NASH), which is being increasingly recognized in Asia, in non-obese mice. METHODS: A methionine-choline-deficient diet(MCD) along with exendin-4(20 μg/kg per day, ip), a GLP-1 analogue, or saline was administered to male db/db mice(non-obese NASH model). Four or eight weeks after commencement of the diet, the mice were sacrificed and their livers were excised. The excised livers were examined by histochemistry for evidence of hepatic steatosis and inflammation. Hepatic triglyceride(TG) and free fatty acid(FFA) content was measured, and the expression of hepatic fat metabolism- and inflammation-related genes was evaluated. Oxidative stress-related parameters and macrophage recruitment were also examined using immunohistochemistry.RESULTS: Four weeks of MCD feeding induced hepatic steatosis and inflammation and increased the hepatic TG and FFA content. The expression of fattyacid transport protein 4(FATP4), a hepatic FFA influxrelated gene; macrophage recruitment; and the level of malondialdehyde(MDA), an oxidative stress marker, were significantly augmented by a 4-wk MCD. The levels of hepatic sterol regulatory element-binding protein-1c(SREBP-1c) m RNA(lipogenesis-related gene) and acyl-coenzyme A oxidase 1(ACOX1) m RNA(β-oxidation-related gene) had decreased at 4 wk and further decreased at 8 wk. However, the level of microsomal triglyceride transfer protein m RNA(a lipid excretion-related gene) remained unchanged. The administration of exendin-4 significantly attenuated the MCD-induced increase in hepatic steatosis, hepatic TG and FFA content, and FATP4 expression as well as the MCD-induced augmentation of hepatic inflammation, macrophage recruitment, and MDA levels. Additionally, it further decreased the hepatic SREBP-1c level and alleviated the MCD-mediated inhibition of the ACOX1 m RNA level. CONCLUSION: These results suggest that GLP-1 inhibits hepatic steatosis and inflammation through the inhibition of hepatic FFA influx and oxidative stress in a non-obese NASH model.