Farnesoid X Receptor Agonist Decreases Lipid Accumulation By Promoting Hepatic Fatty Acid Oxidation In Db/Db Mice

The development of type-2 diabetes and its complications is associated with lipid metabolism disorder. Farnesoid X receptor (FXR) has an important role in regulating lipid and glucose metabolism. However, the underlying mechanism of this remains unclear. The present study investigated the role of fexaramine (Fex), an FXR agonist, on lipid metabolism. For this purpose, 6-week-old db/db mice were treated with Fex for 8 weeks via oral gavage and db/db mice treated with corn oil were used as controls. Body weight and food intake were monitored daily and bi-weekly, respectively. A glucose tolerance test was performed during the final week of feeding. Blood samples were obtained for the analysis of lipids and enzymes related to hepatic function, and liver tissues were analyzed by histology and molecular examination. The results indicated that serum and liver triglyceride levels were decreased in db/db mice administered with Fex. Fewer small lipid droplets were observed in the liver. Small heterodimer partner (SHP), a downstream gene of FXR, was upregulated following Fex treatment. The mRNA and protein expression of genes associated with fatty acid oxidation [acetyl coenzyme A carboxylase (ACC), carnitine palmitoyl transferase 1 alpha (CPT1-alpha) and peroxisome proliferator-activated receptor-coactivator-1 alpha] was also increased. Additionally, the expression of AMP-activated protein kinase (AMPK) was also increased. However, the expression of sterol-regulatory element binding protein-1c and fatty acid synthase, which are associated with fatty acid synthesis, was not significantly different. Taken together, the results of the present study suggested that activation of FXR and its downstream gene SHP may induce the AMPK-ACC-CPT1-alpha signaling pathway, which promotes fatty acids oxidation, ultimately achieving its lipid-lowering effect.