Department of Medicine, University of Chicago, Chicago, Illinois, USA.
Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
Obesity (Silver Spring). 2019 May;27(5):803-812. doi: 10.1002/oby.22440. Epub 2019 Apr 1.
The current study investigated whether bile diversion (BD) improves metabolic phenotype under farnesoid X receptor (FXR) deficiency.
BD was performed in high-fat diet (HFD)-fed FXR knockout (FXRko) and wild-type (WT) animals. Metabolic phenotypes, circulating enteroendocrine hormones, total bile acids (BAs) and BA composition, and cecal gut microbiota were analyzed.
FXR-deficient mice were resistant to HFD-induced obesity; however, FXR-deficient mice also developed hyperglycemia and exhibited increased liver weight, liver steatosis, and circulating triglycerides. BD increased circulating total BAs and taurine-b-muricholic acid, which were in line with normalized hyperglycemia and improved glucose tolerance in HFD-fed WT mice. FXR deficiency also increased total BAs and taurine-b-muricholic acid, but these animals remained hyperglycemic. While BD improved metabolic phenotype in HFD-fed FXRko mice, these improvements were not as effective as in WT mice. BD increased liver expression of fibroblast growth factor 21 and peroxisome proliferator-activated receptor γ coactivator-1β and elevated circulating glucagon-like peptide-1 levels in WT mice but not in FXRko mice. FXR deficiency altered gut microbiota composition with a specific increase in phylum Proteobacteria that may act as a possible microbial signature of some diseases. These cellular and molecular changes in FXRko mice may contribute to resistance toward improved metabolism.
FXR signaling plays a pivotal role in improved metabolic phenotype following BD surgery.
本研究旨在探讨胆汁分流（BD）是否能改善法尼醇 X 受体（FXR）缺失时的代谢表型。
在高脂肪饮食（HFD）喂养的 FXR 敲除（FXRko）和野生型（WT）动物中进行 BD。分析代谢表型、循环肠内分泌激素、总胆汁酸（BAs）和 BA 组成以及盲肠肠道微生物群。
FXR 缺失的小鼠对 HFD 诱导的肥胖具有抗性；然而，FXR 缺失的小鼠也出现了高血糖，并表现出肝重增加、肝脂肪变性和循环甘油三酯增加。BD 增加了循环总 BAs 和牛磺胆酸-β-鼠胆酸，这与 HFD 喂养的 WT 小鼠的正常高血糖和改善的葡萄糖耐量一致。FXR 缺失也增加了总 BAs 和牛磺胆酸-β-鼠胆酸，但这些动物仍处于高血糖状态。虽然 BD 改善了 HFD 喂养的 FXRko 小鼠的代谢表型，但这些改善不如 WT 小鼠有效。BD 增加了 WT 小鼠肝脏成纤维细胞生长因子 21 和过氧化物酶体增殖物激活受体 γ 共激活因子 1β 的表达，并升高了循环胰高血糖素样肽 1 的水平，但在 FXRko 小鼠中则没有。FXR 缺失改变了肠道微生物群的组成，特定增加了厚壁菌门，这可能是某些疾病的微生物特征之一。FXRko 小鼠的这些细胞和分子变化可能有助于抵抗改善的代谢。
FXR 信号在 BD 手术后改善代谢表型中起着关键作用。
