Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 110-746, Republic of Korea.
Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 110-746, Republic of Korea.
Metabolism. 2014 Aug;63(8):1041-8. doi: 10.1016/j.metabol.2014.04.011. Epub 2014 May 6.
Hepatokine fibroblast growth factor (FGF) 21 takes part in the regulation of lipid metabolism in the liver and adipose tissue. We investigated whether exendin-4 regulates the expression of FGF21 in the liver, and whether the effects of exendin-4 on the regulation of FGF21 expression are mediated via silent mating type information regulation 2 homolog (SIRT) 1 or SIRT6.
MATERIALS/METHODS: The C57BL/6J mice were fed a low fat diet, high fat diet, or high fat diet with 1 nmol/kg/day exendin-4 intraperitoneal injection for 10 weeks. HepG2 used in vitro study was treated with palmitic aicd (0.4 mM) with or without exendin-4 (100 nM) and FGF21 (50 nM) for 24 hours. The change of FGF21 and its receptors expression by exendin-4 were measured using quantitative real-time RT-PCR and Western blot. The intracellular lipid content in HepG2 cells was evaluated by Oil Red O staining. Inhibition of FGF21, SIRT1 and SIRT6, by 10 nM siRNA was performed to establish the signaling pathway of exendin-4 action in hepatic lipid metabolism.
Exendin-4 increased the expression of FGF21 and its receptors in high fat diet-induced obese mice. In addition, recombinant FGF21 treatment reduced lipid content in palmitic acid-treated HepG2 cells. We also observed significantly decreased expression of peroxisomal proliferator-activated receptor (PPAR) α and medium-chain acyl-coenzyme A dehydrogenase (MCAD) in hepatocytes transfected with FGF21 siRNA. In cells treated with exendin-4, inhibition of SIRT1, but not SIRT6, by siRNA significantly repressed the expression of FGF21 mRNA, whereas decreased SIRT1 expression by inhibition of FGF21 was not observed.
These data suggest that exendin-4 could improve fatty liver by increasing SIRT1-mediated FGF21.
肝细胞因子成纤维细胞生长因子 21（FGF21）参与肝脏和脂肪组织中脂质代谢的调节。本研究旨在探讨胰高血糖素样肽-1 类似物（exendin-4）是否调节肝脏 FGF21 的表达，以及 exendin-4 对 FGF21 表达调节的作用是否通过沉默交配型信息调节 2 同源物（SIRT）1 或 SIRT6 介导。
材料/方法：将 C57BL/6J 小鼠分别用低脂饮食、高脂饮食或高脂饮食加 1 nmol/kg/天 exendin-4 腹腔注射喂养 10 周。体外研究采用棕榈酸（0.4 mM）处理 HepG2 细胞，或用 exendin-4（100 nM）和 FGF21（50 nM）处理 24 小时。采用实时定量 RT-PCR 和 Western blot 检测 exendin-4 对 FGF21 及其受体表达的影响。用油红 O 染色法评估 HepG2 细胞内的脂滴含量。用 10 nM siRNA 抑制 FGF21、SIRT1 和 SIRT6，建立 exendin-4 作用于肝脂代谢的信号通路。
exendin-4 增加了高脂饮食诱导肥胖小鼠肝脏 FGF21 及其受体的表达。此外，重组 FGF21 处理可降低棕榈酸处理的 HepG2 细胞中的脂质含量。我们还观察到，转染 FGF21 siRNA 的肝细胞中过氧化物酶体增殖物激活受体（PPAR）α和中链酰基辅酶 A 脱氢酶（MCAD）的表达明显下降。在 exendin-4 处理的细胞中，siRNA 抑制 SIRT1，但不抑制 SIRT6，可显著抑制 FGF21 mRNA 的表达，而抑制 FGF21 表达则不会导致 SIRT1 表达降低。
这些数据表明，exendin-4 可以通过增加 SIRT1 介导的 FGF21 来改善脂肪肝。
