Lactoferrin promotes bile acid metabolism and reduces hepatic cholesterol deposition by inhibiting the farnesoid X receptor (FXR)-mediated enterohepatic axis
Lactoferrin promotes bile acid metabolism and reduces hepatic cholesterol deposition by inhibiting the farnesoid X receptor (FXR)-mediated enterohepatic axis
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乳铁蛋白通过抑制法呢醇 X 受体 (FXR) 介导的肠肝轴，促进胆汁酸代谢并减少肝脏胆固醇沉积
DOI：
10.1039/c9fo01616c
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发表时间：
2019-11-01
期刊：
影响因子：
6.1
通讯作者：
Qin, Li-Qiang
中科院分区：
文献类型：
--
作者：
Ling, Chen-Jie;Xu, Jia-Ying;Qin, Li-Qiang
工作背景：乳铁蛋白（LF）是一种多功能糖蛋白，具有调节脂质代谢、降低胆固醇、减轻体重、预防动脉粥样硬化等作用。胆汁酸（BA）代谢在清除体内多余的胆固醇中起着重要作用。然而，LF对BA代谢的影响的研究是有限的和不一致的。研究方法：6-8周龄雄性C57 BL/6 J小鼠分别喂饲正常饲料（对照组）、含胆酸盐的高脂/高胆固醇饲料（HFCCD组）、HFCCD和1.0%LF饮水（LF组）8周。测定血清和肝脏脂质谱以及葡萄糖耐量。采用超高效液相色谱-串联质谱法测定粪便中BA的组成。通过RNA分析，分析了肝脏中BA合成酶基因的表达以及肝脏和回肠中法尼醇X受体（FXR）介导的BA负反馈调节途径。结果：HFCCD可导致血清和肝脏胆固醇水平异常。LF干预使血清高密度脂蛋白胆固醇水平显著升高24.9%，肝脏总胆固醇含量显著降低26%。LF处理使每克粪便中BA含量增加109.8%，粪便中BA排泄总量增加153.5%，粪便中结合BA增加87.6%。此外，LF上调肝固醇12 α-羟化酶（CYP 8B 1）基因的表达，该基因表达BA合成的经典途径中的重要酶，以及胆汁酸-CoA氨基酸N-乙酰转移酶（BAAT）基因，该基因负责形成结合的BA。LF抑制了肝肠轴中FXR介导的途径，包括FXR、成纤维细胞生长因子15和成纤维细胞生长因子受体4。结论：LF可改善高脂高胆固醇饮食小鼠肝脏胆固醇沉积。LF升高结合BA水平，抑制回肠FXR和FXR介导的肝肠轴，增加BA的合成和排泄。
Background: Lactoferrin (LF) is a multifunctional glycoprotein that can regulate lipid metabolism, lower cholesterol, reduce body weight, and prevent atherosclerosis. Bile acid (BA) metabolism plays an important role in removing excess cholesterol from the body. However, studies on the effects of LF on BA metabolism are limited and inconsistent. Methods: Male C57BL/6J mice aged 6-8 weeks were fed with a normal diet (control group), high-fat/high-cholesterol diet containing cholate (HFCCD group), or HFCCD and 1.0% LF in drinking water (LF group) for 8 weeks. Serum and hepatic lipid profiles, and glucose tolerance were measured. Fecal BA composition was determined through ultra-high performance liquid chromatography-tandem mass spectrometry. The gene expression of BA synthase in the liver and farnesoid X receptor (FXR)-mediated BA negative feedback regulation pathway in the liver and ileum were analyzed via RNA analysis. Results: HFCCD resulted in abnormal cholesterol levels in the serum and liver. LF intervention significantly increased the serum high-density lipoprotein cholesterol level by 24.9% and decreased the hepatic total cholesterol content by 26%. LF treatment significantly increased the BA content per gram by 109.8%, the total amount of BA excretion by 153.5% and conjugated BAs by 87.6% in the feces. Furthermore, LF upregulated the expression of the hepatic sterol 12 alpha-hydroxylase (CYP8B1) gene, which expresses important enzymes in the classical pathway of BA synthesis, and the bile acid-CoA amino acid N-acetyltransferase (BAAT) gene, which is responsible for the formation of conjugated BAs. The FXR-mediated pathways in the enterohepatic axis, including FXR, fibroblast growth factor 15, and fibroblast growth factor receptor 4, were inhibited by LF. Conclusions: LF ameliorated hepatic cholesterol deposition in mice fed with a high-fat and high cholesterol diet containing cholate. LF elevated the conjugated BA level, inhibited the ileum FXR and FXR-mediated enterohepatic axis, and increased BA synthesis and excretion.