The farnesoid X receptor (FXR) antagonist 7beta-isopropylchenodeoxycholic acid improves glucose metabolism in mice on a Western diet

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F25%3A10504562" target="_blank" >RIV/00216208:11110/25:10504562 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11150/25:10504562 RIV/00216208:11160/25:10504562

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=VoXZs5d5h0" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=VoXZs5d5h0</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.phrs.2025.107950" target="_blank" >10.1016/j.phrs.2025.107950</a>

Jazyk výsledku

angličtina

Název v původním jazyce

The farnesoid X receptor (FXR) antagonist 7beta-isopropylchenodeoxycholic acid improves glucose metabolism in mice on a Western diet

Popis výsledku v původním jazyce

The significant roles of the farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) in regulating metabolic pathways have recently been demonstrated. However, the precise effects of FXR inhibitors on glucose metabolism remain to be elucidated. In this study, we examined the impact of 7beta-isopropylchenodeoxycholic acid (7beta-ipCDCA), a dual FXR antagonist and TGR5 agonist, on impaired glucose metabolism in mice fed a Western diet. The dual FXR antagonistic/TGR5 agonistic activity of 7beta-ipCDCA was confirmed through gene reporter assays. We evaluated its effects on glucose homeostasis using a glucose tolerance test in C57BL/6 mice fed a Western diet supplemented with sugar in drinking water for 24 weeks. The glucose-lowering mechanism was further investigated by measuring GLP-1 release, mRNA expression of glucose transporters, and relevant genes involved in glucose metabolism in intestinal, hepatic, white adipose, and kidney tissues, and in human NCI-H716 and murine GLUTag L cell lines. Additionally, bile acid metabolome and hepatic lipidome analyses were conducted. Results showed that 7beta-ipCDCA improves glucose homeostasis altered by a Western diet in mice via enhanced GLP-1 secretion and decreased expression of glucose transporters in the ileum and kidneys. While its impact on liver function was marginal, 7beta-ipCDCA increased plasma taurocholic acid levels. Furthermore, 7beta-ipCDCA elevated hepatic triacylglycerols in mice on a chow diet, whereas mice on the Western diet were protected from triacylglycerol accumulation. This study highlights the role of FXR in regulating intestinal glucose transporters and GLP-1 secretion, emphasizing the therapeutic potential of combined FXR antagonists/TGR5 agonists in managing hyperglycemia.

Název v anglickém jazyce

The farnesoid X receptor (FXR) antagonist 7beta-isopropylchenodeoxycholic acid improves glucose metabolism in mice on a Western diet

Popis výsledku anglicky

The significant roles of the farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) in regulating metabolic pathways have recently been demonstrated. However, the precise effects of FXR inhibitors on glucose metabolism remain to be elucidated. In this study, we examined the impact of 7beta-isopropylchenodeoxycholic acid (7beta-ipCDCA), a dual FXR antagonist and TGR5 agonist, on impaired glucose metabolism in mice fed a Western diet. The dual FXR antagonistic/TGR5 agonistic activity of 7beta-ipCDCA was confirmed through gene reporter assays. We evaluated its effects on glucose homeostasis using a glucose tolerance test in C57BL/6 mice fed a Western diet supplemented with sugar in drinking water for 24 weeks. The glucose-lowering mechanism was further investigated by measuring GLP-1 release, mRNA expression of glucose transporters, and relevant genes involved in glucose metabolism in intestinal, hepatic, white adipose, and kidney tissues, and in human NCI-H716 and murine GLUTag L cell lines. Additionally, bile acid metabolome and hepatic lipidome analyses were conducted. Results showed that 7beta-ipCDCA improves glucose homeostasis altered by a Western diet in mice via enhanced GLP-1 secretion and decreased expression of glucose transporters in the ileum and kidneys. While its impact on liver function was marginal, 7beta-ipCDCA increased plasma taurocholic acid levels. Furthermore, 7beta-ipCDCA elevated hepatic triacylglycerols in mice on a chow diet, whereas mice on the Western diet were protected from triacylglycerol accumulation. This study highlights the role of FXR in regulating intestinal glucose transporters and GLP-1 secretion, emphasizing the therapeutic potential of combined FXR antagonists/TGR5 agonists in managing hyperglycemia.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

<a href="/cs/project/EH22_008%2F0004607" target="_blank" >EH22_008/0004607: Nové technologie pro translační výzkum ve farmaceutických vědách /NETPHARM</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Pharmacological Research

ISSN

1043-6618

e-ISSN

1096-1186

Svazek periodika

221

Číslo periodika v rámci svazku

NOV

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

13

Strana od-do

107950

Kód UT WoS článku

001576953700002

EID výsledku v databázi Scopus

2-s2.0-105016234769