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鹅去氧胆酸通过FXR调控高脂饮食诱导小鼠肠道GLP-1表达水平改善胰岛素抵抗的作用
Chenodeoxycholic acid improves insulin resistance by FXR-mediated regulation of intestinal GLP-1 in high-fat diet mice
- 陆军军医大学学报 2024年46卷第9期 页码：952-961
- 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：
[易龙, Email: AMU_yilong@tmmu.edu.cnYI Long, Email: AMU_yilong@tmmu.edu.cn
- 基金信息：国家自然科学基金面上项目(82173505)
DOI：10.16016/j.2097-0927.202309152
中图分类号： R589.2;R966;R975.5收稿：2023-09-28，
修回：2023-12-12，
纸质出版：2024-05-15
- 稿件说明：
移动端阅览
李鹏飞, 蒋玲, 候鹏飞, 等. 鹅去氧胆酸通过FXR调控高脂饮食诱导小鼠肠道GLP-1表达水平改善胰岛素抵抗的作用[J]. 陆军军医大学学报, 2024,46(9):952-961.
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.
李鹏飞, 蒋玲, 候鹏飞, 等. 鹅去氧胆酸通过FXR调控高脂饮食诱导小鼠肠道GLP-1表达水平改善胰岛素抵抗的作用[J]. 陆军军医大学学报, 2024,46(9):952-961. DOI： 10.16016/j.2097-0927.202309152.
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
2
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
2
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
-
α
、
IL
-6、
IL
-1
β
、
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
2
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(
P
＜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(
P
＜0.05)；肠道炎性因子
TNF
-
α
、
IL
-6、
IL
-1
β
mRNA表达水平升高(
P
＜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(
P
＜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(
P
＜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(
P
＜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(
P
＜0.05)，以上作用在加入FXR拮抗剂Z-Gug后被明显抑制(
P
＜0.05)。
结论
2
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
2
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
2
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
TG
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
-
α
IL
-6
IL
-1
β
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
2
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 (
P
<
0.05)
enhanced
FXR
expression at mRNA and protein levels
declined
Gcg
mRNA level and GLP-1 secretion level (
P
<
0.05)
increased mRNA levels of intestinal inflammatory factors
TNF
-
α
IL
-6 and
IL
-1
β
(
P
<
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 (
P
<
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 (
P
<
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 (
P
<
0.05)
which were significantly improved after Z-Gug intervention (
P
<
0.05).
Conclusion
2
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
references
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