Mouse trefoil factor 3 ameliorated high-fat-diet-induced hepatic steatosis via increasing peroxisome proliferator-activated receptor-α-mediated fatty acid oxidation

• Published in: American journal of physiology: endocrinology and metabolism 2019-09, Vol.317 (3), p.E436-E445
• Main Authors: Wu, Xiaojie, Zheng, Hongze, Yang, Rui, Luan, Xiying, Zhang, Lingyun, Jin, Qingsong, Jin, Yongjun, Xue, Jiangnan
• Format: Article
• Language: English
• Subjects: Adenoviruses; Animal models; Animals; Biomarkers; Diabetes mellitus; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - therapy; Diet; Diet, High-Fat; Fatty acids; Fatty Acids - metabolism; Fatty liver; Gene expression; Gene Knockdown Techniques; Genetic Therapy; Genotype & phenotype; Hepatocytes - metabolism; High fat diet; Lipogenesis; Lipogenesis - genetics; Liver; Liver - metabolism; Liver diseases; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - therapy; Obesity - metabolism; Oxidation; Oxidation process; Oxidation-Reduction; Phenotypes; PPAR alpha - biosynthesis; PPAR alpha - genetics; Steatosis; Trefoil factor; Trefoil Factor-3 - genetics
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00454.2018

Hepatic trefoil factor 3 (Tff3) was identified as a potential protein for the treatment of diabetes, yet the effect of Tff3 on nonalcoholic fatty liver disease (NAFLD) has never been explored. Here, we found that the expression of hepatic Tff3 was significantly decreased in NAFLD mice models, suggesting that Tff3 was a potential marker gene for NAFLD. Restoring the expression of Tff3 in the liver of NAFLD mice, including diabetic (db), obese (ob/ob), and diet-induced obese mice, with adenovirus-mediated Tff3 ( ) apparently attenuates the fatty liver phenotype. In contrast, adenovirus-mediated knockdown of Tff3 ( ) in C57BL/6J mice results in an obvious fatty liver phenotype. Furthermore, our molecular experiments indicated that hepatic Tff3 could alleviate hepatic steatosis via upregulating the expression of peroxisome proliferator-activated receptor-α ( ) directly, thereby enhancing the fatty acid oxidation process in the liver. Notably, we found that Tff3 attenuates the fatty liver phenotype independent of modulation of lipogenesis and improves the capacity of anti-inflammation. Overall, our results suggested that hepatic Tff3 could be effectively used as a potential therapy target for the treatment of NAFLD.