高脂肪致肥胖饮食中添加胆酸可通过成纤维细胞生长因子 21 依赖机制抑制小鼠肝三酰甘油蓄积。
Cholic Acid Supplementation of a High-Fat Obesogenic Diet Suppresses Hepatic Triacylglycerol Accumulation in Mice via a Fibroblast Growth Factor 21-Dependent Mechanism.
机构信息
Department of Biochemistry, West Virginia University, Morgantown, WV.
Chemistry Department, Indiana University, Bloomington, IN.
出版信息
J Nutr. 2018 Apr 1;148(4):510-517. doi: 10.1093/jn/nxy022.
BACKGROUND
Supplementation of a high-fat obesogenic diet (HFD) with cholic acid (CA) suppresses the development of obesity, insulin resistance, and hepatic steatosis in mice.
OBJECTIVE
We investigated the role of fibroblast growth factor 21 (FGF21) in mediating the beneficial actions of CA on metabolic syndrome.
METHODS
Male 7-wk-old wild-type (WT) mice and FGF21 knockout (FGF21KO) mice were fed an HFD for 12 wk followed by a 4-wk period in which the mice were fed the HFD alone or supplemented with 0.5% CA. Body composition, gross energy efficiency, glucose tolerance, homeostasis model assessment of insulin resistance (HOMA-IR), and hepatic triacylglycerol (TG) concentrations were measured.
RESULTS
CA administration improved glucose tolerance and decreased total body fat accretion, gross energy efficiency, fasting blood glucose concentrations, and HOMA-IR in both WT mice and FGF21KO mice. The extent of the effect of CA on glucose tolerance, fasting blood glucose concentrations, and HOMA-IR was similar in both mouse strains, whereas the extent of the effect of CA on total body fat accretion and gross energy efficiency was 4.2- to 4.4-fold greater in FGF21KO mice than in WT mice. Further analyses showed that CA decreased hepatic TG concentrations in WT mice (49%) but had no effect on hepatic TG concentrations in FGF21KO mice. CA decreased the activation state of hepatic acetyl-CoA carboxylase 1 (ACC1) and adipose tissue hormone-sensitive lipase (HSL) in WT mice but was not effective in decreasing the activation of ACC1 and HSL in FGF21KO mice.
CONCLUSIONS
FGF21 signaling is required for the beneficial effect of CA on hepatic TG accumulation in mice fed an HFD. We propose that FGF21 signaling potentiates the ability of CA to decrease the activation of ACC1 and HSL, key enzymes controlling the supply of long-chain fatty acid precursors for hepatic TG synthesis.
背景
在高脂肪致肥胖饮食（HFD）中补充胆酸（CA）可抑制小鼠肥胖、胰岛素抵抗和肝脂肪变性的发展。
目的
我们研究了成纤维细胞生长因子 21（FGF21）在介导 CA 对代谢综合征有益作用中的作用。
方法
雄性 7 周龄野生型（WT）和 FGF21 敲除（FGF21KO）小鼠喂食 HFD 12 周，然后再喂食 HFD 4 周，同时补充 0.5% CA。测量体成分、总能量效率、葡萄糖耐量、稳态模型评估胰岛素抵抗（HOMA-IR）和肝三酰甘油（TG）浓度。
结果
CA 给药改善了葡萄糖耐量，减少了 WT 小鼠和 FGF21KO 小鼠的总体脂肪堆积、总能量效率、空腹血糖浓度和 HOMA-IR。CA 对葡萄糖耐量、空腹血糖浓度和 HOMA-IR 的影响在两种小鼠品系中相似，而 CA 对总体脂肪堆积和总能量效率的影响在 FGF21KO 小鼠中比 WT 小鼠高 4.2-4.4 倍。进一步分析表明，CA 降低了 WT 小鼠的肝 TG 浓度（49%），但对 FGF21KO 小鼠的肝 TG 浓度没有影响。CA 降低了 WT 小鼠肝乙酰辅酶 A 羧化酶 1（ACC1）和脂肪组织激素敏感脂肪酶（HSL）的激活状态，但对 FGF21KO 小鼠的 ACC1 和 HSL 激活没有作用。
结论
FGF21 信号传导是 CA 对 HFD 喂养小鼠肝 TG 积累有益作用所必需的。我们提出 FGF21 信号传导增强了 CA 降低 ACC1 和 HSL 激活的能力，ACC1 和 HSL 是控制肝 TG 合成的长链脂肪酸前体供应的关键酶。
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