Ferroptosis resistance cooperates with cellular senescence in the overt stage of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis
Cellular senescence and ferroptosis are the two main, fine-tuned processes in tissue damage restraint; however, they can be overactivated in pathologies such as nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH), becoming dangerous stimuli. Senescence is characterized by a d...
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| Format: | Article |
| Language: | English |
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PAGEPress Publications
2022-06-01
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| Series: | European Journal of Histochemistry |
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| Online Access: | https://ejh.it/index.php/ejh/article/view/3391 |
| _version_ | 1811241703247446016 |
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| author | Antonella Vetuschi Alfredo Cappariello Paolo Onori Eugenio Gaudio Giovanni Latella Simona Pompili Roberta Sferra |
| author_facet | Antonella Vetuschi Alfredo Cappariello Paolo Onori Eugenio Gaudio Giovanni Latella Simona Pompili Roberta Sferra |
| author_sort | Antonella Vetuschi |
| collection | DOAJ |
| description |
Cellular senescence and ferroptosis are the two main, fine-tuned processes in tissue damage restraint; however, they can be overactivated in pathologies such as nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH), becoming dangerous stimuli. Senescence is characterized by a decline in cell division and an abnormal release of reactive oxygen species (ROS), and ferroptosis is represented by iron deposition associated with an excessive accumulation of ROS. ROS and cellular stress pathways are also drivers of NAFLD/NASH development. The etiology of NAFLD/NASH lies in poor diets enriched in fat and sugar. This food regimen leads to liver steatosis, resulting in progressive degeneration of the organ, with a late onset of irreversible fibrosis and cirrhosis. Few studies have investigated the possible connection between senescence and ferroptosis in NAFLD/NASH progression, despite the two events sharing some molecular players. We hypothesized a possible link between senescence and ferroptosis in a NAFLD background. To thoroughly investigate this in the context of “Western-style” diet (WSD) abuse, we used an amylin-modified liver NASH mouse model. The main NASH hallmarks have been confirmed in this model, as well as an increase in apoptosis, and Ki67 and p53 expression in the liver. Senescent beta-galactosidase-positive cells were elevated, as well as the expression of the related secretory molecules Il-6 and MMP-1. Features of DNA damage and iron-overload were found in the livers of NASH mice. Gpx4 (glutathione peroxidase 4) expression, counteracting ferroptotic cell death, was increased. Notably, an increased number of senescent cells showing overexpression of gpx4 was also found. Our data seem to suggest that senescent cells acquire a gpx4-mediated mechanism of ferroptosis resistance and thus remain in the liver, fostering the deterioration of liver fitness.
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| first_indexed | 2024-04-12T13:40:26Z |
| format | Article |
| id | doaj.art-712f27abf1b642d19f96ebe16455a630 |
| institution | Directory Open Access Journal |
| issn | 1121-760X 2038-8306 |
| language | English |
| last_indexed | 2024-04-12T13:40:26Z |
| publishDate | 2022-06-01 |
| publisher | PAGEPress Publications |
| record_format | Article |
| series | European Journal of Histochemistry |
| spelling | doaj.art-712f27abf1b642d19f96ebe16455a6302022-12-22T03:30:52ZengPAGEPress PublicationsEuropean Journal of Histochemistry1121-760X2038-83062022-06-0166310.4081/ejh.2022.3391Ferroptosis resistance cooperates with cellular senescence in the overt stage of nonalcoholic fatty liver disease/nonalcoholic steatohepatitisAntonella Vetuschi0Alfredo Cappariello1Paolo Onori2Eugenio Gaudio3Giovanni Latella4Simona Pompili5Roberta Sferra6Department of Biotechnological and Applied Clinical Sciences, University of L’AquilaDepartment of Biotechnological and Applied Clinical Sciences, University of L’AquilaDepartment of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of RomeDepartment of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of RomeDepartment of Life, Health and Environmental Sciences, Gastroenterology, Hepatology and Nutrition Division, University of L’AquilaDepartment of Biotechnological and Applied Clinical Sciences, University of L’AquilaDepartment of Biotechnological and Applied Clinical Sciences, University of L’Aquila Cellular senescence and ferroptosis are the two main, fine-tuned processes in tissue damage restraint; however, they can be overactivated in pathologies such as nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH), becoming dangerous stimuli. Senescence is characterized by a decline in cell division and an abnormal release of reactive oxygen species (ROS), and ferroptosis is represented by iron deposition associated with an excessive accumulation of ROS. ROS and cellular stress pathways are also drivers of NAFLD/NASH development. The etiology of NAFLD/NASH lies in poor diets enriched in fat and sugar. This food regimen leads to liver steatosis, resulting in progressive degeneration of the organ, with a late onset of irreversible fibrosis and cirrhosis. Few studies have investigated the possible connection between senescence and ferroptosis in NAFLD/NASH progression, despite the two events sharing some molecular players. We hypothesized a possible link between senescence and ferroptosis in a NAFLD background. To thoroughly investigate this in the context of “Western-style” diet (WSD) abuse, we used an amylin-modified liver NASH mouse model. The main NASH hallmarks have been confirmed in this model, as well as an increase in apoptosis, and Ki67 and p53 expression in the liver. Senescent beta-galactosidase-positive cells were elevated, as well as the expression of the related secretory molecules Il-6 and MMP-1. Features of DNA damage and iron-overload were found in the livers of NASH mice. Gpx4 (glutathione peroxidase 4) expression, counteracting ferroptotic cell death, was increased. Notably, an increased number of senescent cells showing overexpression of gpx4 was also found. Our data seem to suggest that senescent cells acquire a gpx4-mediated mechanism of ferroptosis resistance and thus remain in the liver, fostering the deterioration of liver fitness. https://ejh.it/index.php/ejh/article/view/3391NAFLD/NASHsenescenceferroptosisbeta-galactosidasegpx4 |
| spellingShingle | Antonella Vetuschi Alfredo Cappariello Paolo Onori Eugenio Gaudio Giovanni Latella Simona Pompili Roberta Sferra Ferroptosis resistance cooperates with cellular senescence in the overt stage of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis European Journal of Histochemistry NAFLD/NASH senescence ferroptosis beta-galactosidase gpx4 |
| title | Ferroptosis resistance cooperates with cellular senescence in the overt stage of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis |
| title_full | Ferroptosis resistance cooperates with cellular senescence in the overt stage of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis |
| title_fullStr | Ferroptosis resistance cooperates with cellular senescence in the overt stage of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis |
| title_full_unstemmed | Ferroptosis resistance cooperates with cellular senescence in the overt stage of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis |
| title_short | Ferroptosis resistance cooperates with cellular senescence in the overt stage of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis |
| title_sort | ferroptosis resistance cooperates with cellular senescence in the overt stage of nonalcoholic fatty liver disease nonalcoholic steatohepatitis |
| topic | NAFLD/NASH senescence ferroptosis beta-galactosidase gpx4 |
| url | https://ejh.it/index.php/ejh/article/view/3391 |
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