GLP-2 Improves Hepatic Inflammation and Fibrosis in Mdr2^-/- Mice Via Activation of NR4a1/Nur77 in Hepatic Stellate Cells and Intestinal FXR Signaling.

Fuchs CD, Claudel T, Mlitz V, Riva A, Menz M, Brusilovskaya K, Haller F, Baumgartner M, Königshofer P, Unger LW, Sjöland W, Scharnagl H and 5 more

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Stojakovic T, Busslinger G, Reiberger T, Marschall HU, Trauner M

Cellular and molecular gastroenterology and hepatology10 Aug 2023Cited by 23 (Europe PMC)

PMID37572734PMCIDPMC10522987DOI10.1016/j.jcmgh.2023.08.003PepBankPUB-37572734

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Summary

Background & aimsGlucagon-like peptide (GLP)-2 may exert antifibrotic effects on hepatic stellate cells (HSCs). Thus, we aimed to test whether application of the GLP-2 analogue teduglutide has hepatoprotective and antifibrotic effects in the Mdr2/Abcb4^-/- mouse model of sclerosing cholangitis displaying hepatic inflammation and fibrosis.MethodsMdr2^-/- mice were injected daily for 4 weeks with teduglutide followed by gene expression profiling (bulk liver; isolated HSCs) and immunohistochemistry. Activated HSCs (LX2 cells) and immortalized human hepatocytes and human intestinal organoids were treated with GLP-2. mRNA profiling by reverse transcription polymerase chain reaction and electrophoretic mobility shift assay using cytosolic and nuclear protein extracts was performed.ResultsHepatic inflammation, fibrosis, and reactive cholangiocyte phenotype were improved in GLP-2-treated Mdr2^-/- mice. Primary HSCs isolated from Mdr2^-/- mice and LX2 cells exposed to GLP-2 in vitro displayed significantly increased mRNA expression levels of NR4a1/Nur77 (P < .05). Electrophoretic mobility shift assay revealed an increased nuclear NR4a1 binding after GLP-2 treatment in LX2 cells. Moreover, GLP-2 alleviated the Tgfβ-mediated reduction of NR4a1 nuclear binding activity. In vivo, GLP-2 treatment of Mdr2^-/- mice resulted in increased intrahepatic levels of muricholic acids (accordingly Cyp2c70 mRNA expression was significantly increased), and in reduced mRNA levels of Cyp7a1 and FXR. Serum Fgf15 levels were increased in Mdr2^-/- mice treated with GLP-2. Accordingly, GLP-2 treatment of human intestinal organoids activated their FXR-FGF19 signaling axis.ConclusionsGLP-2 treatment increased NR4a1/Nur77 activation in HSCs, subsequently attenuating their activation. GLP-2 promoted intestinal Fxr-Fgf15/19 signaling resulting in reduced Cyp7a1 and increased Cyp2c70 expression in the liver, contributing to hepatoprotective and antifibrotic effects of GLP-2 in the Mdr2^-/- mouse model.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study8

8 results from studies that gave the peptide. No result from this study comes from people.

01AnimalAnimal study (in vivo)Mechanism
In Mdr2-deficient mice, teduglutide improved hepatic inflammation.
In plain wordsIn mice with Mdr2 deficiency, teduglutide reduced liver inflammation.
Peptide
Teduglutide
Outcome
DecreaseHepatic inflammation
Study
mousen: not reported in source
Mdr2/Abcb4 knockout sclerosing cholangitis
Outcome group
Liver fat and liver function · Liver
Studied dose
Dose not stated · 4 weeksAs given in this study (mouse).
Source sentences
Summary
Hepatic inflammation, fibrosis, and reactive cholangiocyte phenotype were improved in GLP-2-treated Mdr2^-/- mice.
1 context sentence(design, population, supporting numbers)
Summary · context
Mdr2^-/- mice were injected daily for 4 weeks with teduglutide followed by gene expression profiling (bulk liver; isolated HSCs) and immunohistochemistry.
Show in the study text Report a problemFND-3757273401
02AnimalAnimal study (in vivo)Mechanism
In Mdr2-deficient mice, teduglutide improved hepatic fibrosis.
In plain wordsIn mice with Mdr2 deficiency, teduglutide reduced liver fibrosis.
Peptide
Teduglutide
Outcome
DecreaseHepatic fibrosis
Study
mousen: not reported in source
Mdr2/Abcb4 knockout sclerosing cholangitis
Outcome group
Liver fat and liver function · Liver
Studied dose
Dose not stated · 4 weeksAs given in this study (mouse).
Source sentences
Summary
Hepatic inflammation, fibrosis, and reactive cholangiocyte phenotype were improved in GLP-2-treated Mdr2^-/- mice.
1 context sentence(design, population, supporting numbers)
Summary · context
Mdr2^-/- mice were injected daily for 4 weeks with teduglutide followed by gene expression profiling (bulk liver; isolated HSCs) and immunohistochemistry.
Show in the study text Report a problemFND-3757273402
03AnimalAnimal study (in vivo)Mechanism
In Mdr2-deficient mice, teduglutide improved the reactive cholangiocyte phenotype.
In plain wordsIn mice with Mdr2 deficiency, teduglutide improved the abnormal bile-duct cell phenotype.
Peptide
Teduglutide
Outcome
DecreaseReactive cholangiocyte phenotype
Study
mousen: not reported in source
Mdr2/Abcb4 knockout sclerosing cholangitis
Outcome group
Liver fat and liver function · Liver
Studied dose
Dose not stated · 4 weeksAs given in this study (mouse).
Source sentences
Summary
Hepatic inflammation, fibrosis, and reactive cholangiocyte phenotype were improved in GLP-2-treated Mdr2^-/- mice.
1 context sentence(design, population, supporting numbers)
Summary · context
Mdr2^-/- mice were injected daily for 4 weeks with teduglutide followed by gene expression profiling (bulk liver; isolated HSCs) and immunohistochemistry.
Show in the study text Report a problemFND-3757273403
04AnimalAnimal study (in vivo)Mechanism
In Mdr2-deficient mice, teduglutide increased intrahepatic muricholic acids.
In plain wordsIn mice with Mdr2 deficiency, teduglutide increased muricholic acids in the liver.
Peptide
Teduglutide
Outcome
IncreaseIntrahepatic muricholic acids
Study
mousen: not reported in source
Mdr2/Abcb4 knockout sclerosing cholangitis
Outcome group
Liver fat and liver function · Liver
Studied dose
Dose not stated · 4 weeksAs given in this study (mouse).
Source sentences
Summary
In vivo, GLP-2 treatment of Mdr2^-/- mice resulted in increased intrahepatic levels of muricholic acids (accordingly Cyp2c70 mRNA expression was significantly increased), and in reduced mRNA levels of Cyp7a1 and FXR.
1 context sentence(design, population, supporting numbers)
Summary · context
Mdr2^-/- mice were injected daily for 4 weeks with teduglutide followed by gene expression profiling (bulk liver; isolated HSCs) and immunohistochemistry.
Show in the study text Report a problemFND-3757273404
05AnimalAnimal study (in vivo)Mechanism
In Mdr2-deficient mice, teduglutide significantly increased Cyp2c70 mRNA expression.
In plain wordsIn mice with Mdr2 deficiency, teduglutide increased liver Cyp2c70 gene expression.
Peptide
Teduglutide
Outcome
IncreaseCyp2c70 mRNA
Study
mousen: not reported in source
Mdr2/Abcb4 knockout sclerosing cholangitis
Outcome group
Liver fat and liver function · Liver
Studied dose
Dose not stated · 4 weeksAs given in this study (mouse).
Source sentences
Summary
In vivo, GLP-2 treatment of Mdr2^-/- mice resulted in increased intrahepatic levels of muricholic acids (accordingly Cyp2c70 mRNA expression was significantly increased), and in reduced mRNA levels of Cyp7a1 and FXR.
1 context sentence(design, population, supporting numbers)
Summary · context
Mdr2^-/- mice were injected daily for 4 weeks with teduglutide followed by gene expression profiling (bulk liver; isolated HSCs) and immunohistochemistry.
Show in the study text Report a problemFND-3757273405
06AnimalAnimal study (in vivo)Mechanism
In Mdr2-deficient mice, teduglutide reduced Cyp7a1 mRNA levels.
In plain wordsIn mice with Mdr2 deficiency, teduglutide reduced liver Cyp7a1 gene expression.
Peptide
Teduglutide
Outcome
DecreaseCyp7a1 mRNA
Study
mousen: not reported in source
Mdr2/Abcb4 knockout sclerosing cholangitis
Outcome group
Liver fat and liver function · Liver
Studied dose
Dose not stated · 4 weeksAs given in this study (mouse).
Source sentences
Summary
In vivo, GLP-2 treatment of Mdr2^-/- mice resulted in increased intrahepatic levels of muricholic acids (accordingly Cyp2c70 mRNA expression was significantly increased), and in reduced mRNA levels of Cyp7a1 and FXR.
1 context sentence(design, population, supporting numbers)
Summary · context
Mdr2^-/- mice were injected daily for 4 weeks with teduglutide followed by gene expression profiling (bulk liver; isolated HSCs) and immunohistochemistry.
Show in the study text Report a problemFND-3757273406
07AnimalAnimal study (in vivo)Mechanism
In Mdr2-deficient mice, teduglutide reduced FXR mRNA levels.
In plain wordsIn mice with Mdr2 deficiency, teduglutide reduced liver FXR gene expression.
Peptide
Teduglutide
Outcome
DecreaseFXR mRNA
Study
mousen: not reported in source
Mdr2/Abcb4 knockout sclerosing cholangitis
Outcome group
Liver fat and liver function · Liver
Studied dose
Dose not stated · 4 weeksAs given in this study (mouse).
Source sentences
Summary
In vivo, GLP-2 treatment of Mdr2^-/- mice resulted in increased intrahepatic levels of muricholic acids (accordingly Cyp2c70 mRNA expression was significantly increased), and in reduced mRNA levels of Cyp7a1 and FXR.
1 context sentence(design, population, supporting numbers)
Summary · context
Mdr2^-/- mice were injected daily for 4 weeks with teduglutide followed by gene expression profiling (bulk liver; isolated HSCs) and immunohistochemistry.
Show in the study text Report a problemFND-3757273407
08AnimalAnimal study (in vivo)Mechanism
In Mdr2-deficient mice, teduglutide increased serum Fgf15 levels.
In plain wordsIn mice with Mdr2 deficiency, teduglutide increased blood Fgf15 levels.
Peptide
Teduglutide
Outcome
IncreaseSerum Fgf15
Study
mousen: not reported in source
Mdr2/Abcb4 knockout sclerosing cholangitis
Outcome group
Liver fat and liver function · Liver
Studied dose
Dose not stated · 4 weeksAs given in this study (mouse).
Source sentences
Summary
Serum Fgf15 levels were increased in Mdr2^-/- mice treated with GLP-2.
1 context sentence(design, population, supporting numbers)
Summary · context
Mdr2^-/- mice were injected daily for 4 weeks with teduglutide followed by gene expression profiling (bulk liver; isolated HSCs) and immunohistochemistry.
Show in the study text Report a problemFND-3757273408

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
28 Oct 2026, 02:03 UTC
Study results updated
Version 1
27 Oct 2026, 16:37 UTC
First added · source update from Europe PMC

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