Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China.
Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100191, P.R. China.
Int J Mol Med. 2018 Sep;42(3):1723-1731. doi: 10.3892/ijmm.2018.3715. Epub 2018 Jun 5.
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 1α (CPT1‑α) and peroxisome proliferator‑activated receptor‑coactivator‑1α] 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‑α signaling pathway, which promotes fatty acids oxidation, ultimately achieving its lipid‑lowering effect.
2 型糖尿病及其并发症的发展与脂质代谢紊乱有关。法尼醇 X 受体 (FXR) 在调节脂质和葡萄糖代谢方面起着重要作用。然而，其潜在机制尚不清楚。本研究探讨了 FXR 激动剂非诺贝特（Fex）对脂质代谢的作用。为此，通过口服灌胃用 Fex 处理 6 周龄 db/db 小鼠 8 周，并将用玉米油处理的 db/db 小鼠作为对照。每天监测体重和每周两次监测食物摄入量。在喂养的最后一周进行葡萄糖耐量试验。采集血液样本分析与肝功能相关的脂质和酶，并通过组织学和分子检查分析肝组织。结果表明，给予 Fex 的 db/db 小鼠血清和肝脏甘油三酯水平降低。肝脏中观察到的小脂滴减少。FXR 的下游基因小异二聚体伴侣（SHP）在 Fex 处理后上调。与脂肪酸氧化相关的基因（乙酰辅酶 A 羧化酶（ACC）、肉碱棕榈酰转移酶 1α（CPT1-α）和过氧化物酶体增殖物激活受体-共激活因子-1α）的 mRNA 和蛋白表达也增加。此外，AMP 激活的蛋白激酶（AMPK）的表达也增加。然而，与脂肪酸合成相关的固醇调节元件结合蛋白-1c 和脂肪酸合酶的表达没有显著差异。综上所述，本研究结果表明，FXR 及其下游基因 SHP 的激活可能诱导 AMPK-ACC-CPT1-α 信号通路，促进脂肪酸氧化，最终达到其降血脂作用。
