Chenodeoxycholic acid improves insulin resistance by FXR-mediated regulation of intestinal GLP-1 in high-fat diet mice

Pengfei LI; Ling JIANG; Pengfei HOU; Niu DONG; Mantian MI; Long YI

doi:10.16016/j.2097-0927.202309152

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Chenodeoxycholic acid improves insulin resistance by FXR-mediated regulation of intestinal GLP-1 in high-fat diet mice

Public Health and Preventive Medicine | 更新时间：2026-01-09

- Chenodeoxycholic acid improves insulin resistance by FXR-mediated regulation of intestinal GLP-1 in high-fat diet mice
- Journal of Army Medical University Vol. 46, Issue 9, Pages: 952-961(2024)
- 作者机构：
  
  400038 重庆，陆军军医大学(第三军医大学)军事预防医学系营养与食品安全研究中心，重庆市医学营养研究中心，营养与健康重庆市重点实验室
- 作者简介：
- 基金信息：
  
  the General Program of National Natural Science Foundation of China(82173505)
- DOI：10.16016/j.2097-0927.202309152
  CLC： R589.2;R966;R975.5
- Received：28 September 2023，
  
  Revised：2023-12-12，
  
  Published：15 May 2024
- 稿件说明：
移动端阅览
Pengfei LI, Ling JIANG, Pengfei HOU, et al. Chenodeoxycholic acid improves insulin resistance by FXR-mediated regulation of intestinal GLP-1 in high-fat diet mice[J]. Journal of Army Medical University, 2024, 46(9): 952-961.
DOI：

Pengfei LI, Ling JIANG, Pengfei HOU, et al. Chenodeoxycholic acid improves insulin resistance by FXR-mediated regulation of intestinal GLP-1 in high-fat diet mice[J]. Journal of Army Medical University, 2024, 46(9): 952-961. DOI： 10.16016/j.2097-0927.202309152.

摘要

目的

探究鹅去氧胆酸(chenodeoxycholic acid，CDCA)通过FXR对高脂饮食诱导小鼠肠道GLP-1表达水平的影响及相关机制。

方法

C57BL/6小鼠40只分为对照组(Control组)、高脂饮食组(HFD组)、HFD+CDCA组、HFD+Z-Gug(FXR拮抗剂)组、HFD+CDCA+Z-Gug组，每组8只。干预8周，期间每周检测体质量及24 h摄食量。第8周进行口服葡萄糖耐量实验(OGTT)、腹腔葡萄糖耐量实验(IPGTT)。小鼠处死后，检测血清学指标GLu、TG、CHO、LDL-C、HDL-C；免疫荧光检测小鼠肠道组织GLP-1及FXR表达水平；RT-qPCR检测炎性因子

TNF

、

-6、

-1

、

Gcg

及

FXR

mRNA表达；ELISA试剂盒检测血清GLP-1含量；流式细胞术检测小肠IELs亚群比例及CD26/DPP4表达水平。

结果

与Control组相比，HFD组小鼠体质量增加，血清糖脂代谢异常，口服糖耐量受损，胃肠激素分泌减弱(

＜0.05)；

FXR

mRNA及蛋白表达水平增加，

Gcg

mRNA表达及GLP-1分泌水平下降(

＜0.05)；肠道炎性因子

TNF

、

-6、

-1

mRNA表达水平升高(

＜0.05)；TCRαβ

IELs、TCRαβ

CD8αα

IELs与TCRαβ

CD8αβ

IELs细胞比例增加，TCRγδ

IELs比例下降，IELs总CD26/DPP4表达增加(

＜0.05)。与HFD组相比，HFD+CDCA组小鼠体质量增加，口服糖耐量异常，胃肠激素分泌减弱(

＜0.05)；肠组织

FXR

mRNA及蛋白表达增加，

Gcg

mRNA表达及GLP-1分泌降低(

＜0.05)；肠道炎性因子表达降低，TCRαβ

IELs、TCRαβ

CD8αα

IELs与TCRαβ

CD8αβ

IELs细胞比例下降，TCRγδ

IELs占IELs比例升高，IELs总CD26/DPP4表达升高(

＜0.05)，以上作用在加入FXR拮抗剂Z-Gug后被明显抑制(

＜0.05)。

结论

CDCA可能通过激活FXR受体抑制肠道组织GLP-1表达，减少GLP-1分泌；同时可能抑制相关炎症因子表达调节IELs亚群比例，上调CD26/DPP4表达水平，促进GLP-1降解，加重胰岛素抵抗。

Abstract

Objective

To explore the effect of chenodeoxycholic acid (CDCA) on the expression of glucagon-like peptide-1 (GLP-1) in the intestine of mice induced by high-fat diet (HFD) through farnesoid X receptor (FXR)

and investigate the related mechanism.

Methods

Forty C57BL/6 mice were divided into control group

HFD group

HFD+CDCA group

HFD+Z-Gug (FXR antagonist) group

and HFD+CDCA+Z-Gug group

with 8 animals in each group. During intervention for 8 weeks

body weight and 24-hour food intake were measured every week. At the 8th week

oral glucose tolerance test (OGTT) and intraperitoneal glucose tolerance test (IPGTT) were conducted. After the mice were sacrificed

the serum levels of GLu

CHO

LDL-C and HDL-C were detected; the expression levels of GLP-1

and FXR in intestinal tissues were detected by immunofluorescence assay; and the mRNA levels of

TNF

-6

-1

Gcg

and

FXR

were detected by RT-qPCR; the serum level of GLP-1 was detected by ELISA

and the proportion of intraepithelial lymphocytes (IELs) subsets and the expression of CD26/DPP4 were detected by flow cytometry.

Results

Compared with the control group

the HFD group had increased body weight

abnormal serum glucose and lipid metabolism

impaired oral glucose tolerance

and weakened secretion of gastrointestinal hormones (

0.05)

enhanced

FXR

expression at mRNA and protein levels

declined

Gcg

mRNA level and GLP-1 secretion level (

0.05)

increased mRNA levels of intestinal inflammatory factors

TNF

-6 and

-1

(

0.05)

raised proportions of TCRαβ

IELs

TCRαβ

CD8αα

IELs

and TCRαβ

CD8αβ

IELs but reduced proportion of TCRγδ

IELs

and increased total CD26/DPP4 expression in IELs (

0.05). Compared with the HFD group

HFD+CDCA treatment resulted in significantly increased body weight

impaired oral glucose tolerance

decreased secretion of gastrointestinal hormones

increased

FXR

mRNA and protein expression

and decreased

Gcg

mRNA expression and GLP-1 secretion (

0.05); decreased proportions of TCRαβ

IELs

TCRαβ

CD8αα

IELs and TCRααβ

CD8αβ

IELs but increased proportion of TCRγδ

cells in IELs

and increased expression of total CD26/DPP4 in IELs (

0.05)

which were significantly improved after Z-Gug intervention (

0.05).

Conclusion

CDCA may inhibit the expression and secretion of GLP-1 in intestinal tissue by activating FXR

and reduce the secretion of GLP-1. At the same time

CDCA may inhibit the expression of related inflammatory factors

regulate the proportions of IELs subsets

up-regulate the expression level of CD26/DPP4

promote the degradation of GLP-1 and aggravate insulin resistance.

关键词

Keywords

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