Cargando…

Association of Differentially Altered Liver Fibrosis with Deposition of TGFBi in Stabilin-Deficient Mice

Liver sinusoidal endothelial cells (LSECs) control clearance of Transforming growth factor, beta-induced, 68kDa (TGFBi) and Periostin (POSTN) through scavenger receptors Stabilin-1 (Stab1) and Stabilin-2 (Stab2). Stabilin inhibition can ameliorate atherosclerosis in mouse models, while Stabilin-doub...

Descripción completa

Detalles Bibliográficos
Autores principales: Krzistetzko, Jessica, Géraud, Cyrill, Dormann, Christof, Riedel, Anna, Leibing, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10341388/
https://www.ncbi.nlm.nih.gov/pubmed/37446152
http://dx.doi.org/10.3390/ijms241310969
_version_ 1785072249994215424
author Krzistetzko, Jessica
Géraud, Cyrill
Dormann, Christof
Riedel, Anna
Leibing, Thomas
author_facet Krzistetzko, Jessica
Géraud, Cyrill
Dormann, Christof
Riedel, Anna
Leibing, Thomas
author_sort Krzistetzko, Jessica
collection PubMed
description Liver sinusoidal endothelial cells (LSECs) control clearance of Transforming growth factor, beta-induced, 68kDa (TGFBi) and Periostin (POSTN) through scavenger receptors Stabilin-1 (Stab1) and Stabilin-2 (Stab2). Stabilin inhibition can ameliorate atherosclerosis in mouse models, while Stabilin-double-knockout leads to glomerulofibrosis. Fibrotic organ damage may pose a limiting factor in future anti-Stabilin therapies. While Stab1-deficient (Stab1−/−) mice were shown to exhibit higher liver fibrosis levels upon challenges, fibrosis susceptibility has not been studied in Stab2-deficient (Stab2−/−) mice. Wildtype (WT), Stab1−/− and Stab2−/− mice were fed experimental diets, and local ligand abundance, hepatic fibrosis, and ligand plasma levels were measured. Hepatic fibrosis was increased in both Stab1−/− and Stab2−/− at baseline. A pro-fibrotic short Methionine-Choline-deficient (MCD) diet induced slightly increased liver fibrosis in Stab1−/− and Stab2−/− mice. A Choline-deficient L-amino acid-defined (CDAA) diet induced liver fibrosis of similar distribution and extent in all genotypes (WT, Stab1−/− and Stab2−/−). A hepatic abundance of Stabilin ligand TGFBi correlated very highly with liver fibrosis levels. In contrast, plasma levels of TGFBi were increased only in Stab2−/− mice after the CDAA diet but not the MCD diet, indicating the differential effects of these diets. Here we show that a single Stabilin deficiency of either Stab1 or Stab2 induces mildly increased collagen depositions under homeostatic conditions. Upon experimental dietary challenge, the local abundance of Stabilin ligand TGFBi was differentially altered in Stabilin-deficient mice, indicating differentially affected LSEC scavenger functions. Since anti-Stabilin-directed therapies are in clinical evaluation for the treatment of diseases, these findings bear relevance to treatment with novel anti-Stabilin agents.
format Online
Article
Text
id pubmed-10341388
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-103413882023-07-14 Association of Differentially Altered Liver Fibrosis with Deposition of TGFBi in Stabilin-Deficient Mice Krzistetzko, Jessica Géraud, Cyrill Dormann, Christof Riedel, Anna Leibing, Thomas Int J Mol Sci Article Liver sinusoidal endothelial cells (LSECs) control clearance of Transforming growth factor, beta-induced, 68kDa (TGFBi) and Periostin (POSTN) through scavenger receptors Stabilin-1 (Stab1) and Stabilin-2 (Stab2). Stabilin inhibition can ameliorate atherosclerosis in mouse models, while Stabilin-double-knockout leads to glomerulofibrosis. Fibrotic organ damage may pose a limiting factor in future anti-Stabilin therapies. While Stab1-deficient (Stab1−/−) mice were shown to exhibit higher liver fibrosis levels upon challenges, fibrosis susceptibility has not been studied in Stab2-deficient (Stab2−/−) mice. Wildtype (WT), Stab1−/− and Stab2−/− mice were fed experimental diets, and local ligand abundance, hepatic fibrosis, and ligand plasma levels were measured. Hepatic fibrosis was increased in both Stab1−/− and Stab2−/− at baseline. A pro-fibrotic short Methionine-Choline-deficient (MCD) diet induced slightly increased liver fibrosis in Stab1−/− and Stab2−/− mice. A Choline-deficient L-amino acid-defined (CDAA) diet induced liver fibrosis of similar distribution and extent in all genotypes (WT, Stab1−/− and Stab2−/−). A hepatic abundance of Stabilin ligand TGFBi correlated very highly with liver fibrosis levels. In contrast, plasma levels of TGFBi were increased only in Stab2−/− mice after the CDAA diet but not the MCD diet, indicating the differential effects of these diets. Here we show that a single Stabilin deficiency of either Stab1 or Stab2 induces mildly increased collagen depositions under homeostatic conditions. Upon experimental dietary challenge, the local abundance of Stabilin ligand TGFBi was differentially altered in Stabilin-deficient mice, indicating differentially affected LSEC scavenger functions. Since anti-Stabilin-directed therapies are in clinical evaluation for the treatment of diseases, these findings bear relevance to treatment with novel anti-Stabilin agents. MDPI 2023-06-30 /pmc/articles/PMC10341388/ /pubmed/37446152 http://dx.doi.org/10.3390/ijms241310969 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Krzistetzko, Jessica
Géraud, Cyrill
Dormann, Christof
Riedel, Anna
Leibing, Thomas
Association of Differentially Altered Liver Fibrosis with Deposition of TGFBi in Stabilin-Deficient Mice
title Association of Differentially Altered Liver Fibrosis with Deposition of TGFBi in Stabilin-Deficient Mice
title_full Association of Differentially Altered Liver Fibrosis with Deposition of TGFBi in Stabilin-Deficient Mice
title_fullStr Association of Differentially Altered Liver Fibrosis with Deposition of TGFBi in Stabilin-Deficient Mice
title_full_unstemmed Association of Differentially Altered Liver Fibrosis with Deposition of TGFBi in Stabilin-Deficient Mice
title_short Association of Differentially Altered Liver Fibrosis with Deposition of TGFBi in Stabilin-Deficient Mice
title_sort association of differentially altered liver fibrosis with deposition of tgfbi in stabilin-deficient mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10341388/
https://www.ncbi.nlm.nih.gov/pubmed/37446152
http://dx.doi.org/10.3390/ijms241310969
work_keys_str_mv AT krzistetzkojessica associationofdifferentiallyalteredliverfibrosiswithdepositionoftgfbiinstabilindeficientmice
AT geraudcyrill associationofdifferentiallyalteredliverfibrosiswithdepositionoftgfbiinstabilindeficientmice
AT dormannchristof associationofdifferentiallyalteredliverfibrosiswithdepositionoftgfbiinstabilindeficientmice
AT riedelanna associationofdifferentiallyalteredliverfibrosiswithdepositionoftgfbiinstabilindeficientmice
AT leibingthomas associationofdifferentiallyalteredliverfibrosiswithdepositionoftgfbiinstabilindeficientmice