Deletion of RAGE fails to prevent hepatosteatosis in obese mice due to impairment of other AGEs receptors and detoxifying systems
Abstract Advanced glycation endproducts (AGEs) are involved in several diseases, including NAFLD and NASH. RAGE is the main receptor mediating the pro-inflammatory signalling induced by AGEs. Therefore, targeting of RAGE has been proposed for prevention of chronic inflammatory diseases. However, the...
Guardado en:
| Autores principales: | , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2021
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/95cedba2ffd84ffbafb3eae79144aabe |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:95cedba2ffd84ffbafb3eae79144aabe |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:95cedba2ffd84ffbafb3eae79144aabe2021-12-02T16:37:37ZDeletion of RAGE fails to prevent hepatosteatosis in obese mice due to impairment of other AGEs receptors and detoxifying systems10.1038/s41598-021-96859-72045-2322https://doaj.org/article/95cedba2ffd84ffbafb3eae79144aabe2021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-96859-7https://doaj.org/toc/2045-2322Abstract Advanced glycation endproducts (AGEs) are involved in several diseases, including NAFLD and NASH. RAGE is the main receptor mediating the pro-inflammatory signalling induced by AGEs. Therefore, targeting of RAGE has been proposed for prevention of chronic inflammatory diseases. However, the role of RAGE in the development of NAFLD and NASH remains poorly understood. We thus aimed to analyse the effect of obesity on AGEs accumulation, AGE-receptors and AGE-detoxification, and whether the absence of RAGE might improve hepatosteatosis and inflammation, by comparing the liver of lean control, obese (LeptrDb−/−) and obese RAGE-deficient (RAGE−/− LeptrDb−/−) mice. Obesity induced AGEs accumulation and RAGE expression with hepatosteatosis and inflammation in LeptrDb−/−, compared to lean controls. Despite the genetic deletion of RAGE in the LeptrDb−/− mice, high levels of intrahepatic AGEs were maintained accompanied by decreased expression of the protective AGE-receptor-1, impaired AGE-detoxifying system glyoxalase-1, and increased expression of the alternative AGE-receptor galectin-3. We also found sustained hepatosteatosis and inflammation as determined by persistent activation of the lipogenic SREBP1c and proinflammatory NLRP3 signalling pathways. Thus, RAGE targeting is not effective in the prevention of NAFLD in conditions of obesity, likely due to the direct liver specific crosstalk of RAGE with other AGE-receptors and AGE-detoxifying systems.Kristiaan WoutersAlessia S. CentoKatrien H. GaensMargee TeunissenJean L. J. M. ScheijenFederica BaruttaFausto ChiazzaDebora CollottaManuela AragnoGabriella GrudenMassimo CollinoCasper G. SchalkwijkRaffaella MastrocolaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Kristiaan Wouters Alessia S. Cento Katrien H. Gaens Margee Teunissen Jean L. J. M. Scheijen Federica Barutta Fausto Chiazza Debora Collotta Manuela Aragno Gabriella Gruden Massimo Collino Casper G. Schalkwijk Raffaella Mastrocola Deletion of RAGE fails to prevent hepatosteatosis in obese mice due to impairment of other AGEs receptors and detoxifying systems |
| description |
Abstract Advanced glycation endproducts (AGEs) are involved in several diseases, including NAFLD and NASH. RAGE is the main receptor mediating the pro-inflammatory signalling induced by AGEs. Therefore, targeting of RAGE has been proposed for prevention of chronic inflammatory diseases. However, the role of RAGE in the development of NAFLD and NASH remains poorly understood. We thus aimed to analyse the effect of obesity on AGEs accumulation, AGE-receptors and AGE-detoxification, and whether the absence of RAGE might improve hepatosteatosis and inflammation, by comparing the liver of lean control, obese (LeptrDb−/−) and obese RAGE-deficient (RAGE−/− LeptrDb−/−) mice. Obesity induced AGEs accumulation and RAGE expression with hepatosteatosis and inflammation in LeptrDb−/−, compared to lean controls. Despite the genetic deletion of RAGE in the LeptrDb−/− mice, high levels of intrahepatic AGEs were maintained accompanied by decreased expression of the protective AGE-receptor-1, impaired AGE-detoxifying system glyoxalase-1, and increased expression of the alternative AGE-receptor galectin-3. We also found sustained hepatosteatosis and inflammation as determined by persistent activation of the lipogenic SREBP1c and proinflammatory NLRP3 signalling pathways. Thus, RAGE targeting is not effective in the prevention of NAFLD in conditions of obesity, likely due to the direct liver specific crosstalk of RAGE with other AGE-receptors and AGE-detoxifying systems. |
| format |
article |
| author |
Kristiaan Wouters Alessia S. Cento Katrien H. Gaens Margee Teunissen Jean L. J. M. Scheijen Federica Barutta Fausto Chiazza Debora Collotta Manuela Aragno Gabriella Gruden Massimo Collino Casper G. Schalkwijk Raffaella Mastrocola |
| author_facet |
Kristiaan Wouters Alessia S. Cento Katrien H. Gaens Margee Teunissen Jean L. J. M. Scheijen Federica Barutta Fausto Chiazza Debora Collotta Manuela Aragno Gabriella Gruden Massimo Collino Casper G. Schalkwijk Raffaella Mastrocola |
| author_sort |
Kristiaan Wouters |
| title |
Deletion of RAGE fails to prevent hepatosteatosis in obese mice due to impairment of other AGEs receptors and detoxifying systems |
| title_short |
Deletion of RAGE fails to prevent hepatosteatosis in obese mice due to impairment of other AGEs receptors and detoxifying systems |
| title_full |
Deletion of RAGE fails to prevent hepatosteatosis in obese mice due to impairment of other AGEs receptors and detoxifying systems |
| title_fullStr |
Deletion of RAGE fails to prevent hepatosteatosis in obese mice due to impairment of other AGEs receptors and detoxifying systems |
| title_full_unstemmed |
Deletion of RAGE fails to prevent hepatosteatosis in obese mice due to impairment of other AGEs receptors and detoxifying systems |
| title_sort |
deletion of rage fails to prevent hepatosteatosis in obese mice due to impairment of other ages receptors and detoxifying systems |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/95cedba2ffd84ffbafb3eae79144aabe |
| work_keys_str_mv |
AT kristiaanwouters deletionofragefailstopreventhepatosteatosisinobesemiceduetoimpairmentofotheragesreceptorsanddetoxifyingsystems AT alessiascento deletionofragefailstopreventhepatosteatosisinobesemiceduetoimpairmentofotheragesreceptorsanddetoxifyingsystems AT katrienhgaens deletionofragefailstopreventhepatosteatosisinobesemiceduetoimpairmentofotheragesreceptorsanddetoxifyingsystems AT margeeteunissen deletionofragefailstopreventhepatosteatosisinobesemiceduetoimpairmentofotheragesreceptorsanddetoxifyingsystems AT jeanljmscheijen deletionofragefailstopreventhepatosteatosisinobesemiceduetoimpairmentofotheragesreceptorsanddetoxifyingsystems AT federicabarutta deletionofragefailstopreventhepatosteatosisinobesemiceduetoimpairmentofotheragesreceptorsanddetoxifyingsystems AT faustochiazza deletionofragefailstopreventhepatosteatosisinobesemiceduetoimpairmentofotheragesreceptorsanddetoxifyingsystems AT deboracollotta deletionofragefailstopreventhepatosteatosisinobesemiceduetoimpairmentofotheragesreceptorsanddetoxifyingsystems AT manuelaaragno deletionofragefailstopreventhepatosteatosisinobesemiceduetoimpairmentofotheragesreceptorsanddetoxifyingsystems AT gabriellagruden deletionofragefailstopreventhepatosteatosisinobesemiceduetoimpairmentofotheragesreceptorsanddetoxifyingsystems AT massimocollino deletionofragefailstopreventhepatosteatosisinobesemiceduetoimpairmentofotheragesreceptorsanddetoxifyingsystems AT caspergschalkwijk deletionofragefailstopreventhepatosteatosisinobesemiceduetoimpairmentofotheragesreceptorsanddetoxifyingsystems AT raffaellamastrocola deletionofragefailstopreventhepatosteatosisinobesemiceduetoimpairmentofotheragesreceptorsanddetoxifyingsystems |
| _version_ |
1718383645857677312 |