Fructose Causes Liver Damage, Polyploidy, and Dysplasia in the Setting of Short Telomeres and p53 Loss
Studies in humans and model systems have established an important role of short telomeres in predisposing to liver fibrosis through pathways that are incompletely understood. Recent studies have shown that telomere dysfunction impairs cellular metabolism, but whether and how these metabolic alterati...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-06-01
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| Series: | Metabolites |
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| Online Access: | https://www.mdpi.com/2218-1989/11/6/394 |
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| author | Christopher Chronowski Viktor Akhanov Doug Chan Andre Catic Milton Finegold Ergün Sahin |
| author_facet | Christopher Chronowski Viktor Akhanov Doug Chan Andre Catic Milton Finegold Ergün Sahin |
| author_sort | Christopher Chronowski |
| collection | DOAJ |
| description | Studies in humans and model systems have established an important role of short telomeres in predisposing to liver fibrosis through pathways that are incompletely understood. Recent studies have shown that telomere dysfunction impairs cellular metabolism, but whether and how these metabolic alterations contribute to liver fibrosis is not well understood. Here, we investigated whether short telomeres change the hepatic response to metabolic stress induced by fructose, a sugar that is highly implicated in non-alcoholic fatty liver disease. We find that telomere shortening in telomerase knockout mice (TKO) imparts a pronounced susceptibility to fructose as reflected in the activation of p53, increased apoptosis, and senescence, despite lower hepatic fat accumulation in TKO mice compared to wild type mice with long telomeres. The decreased fat accumulation in TKO is mediated by p53 and deletion of p53 normalizes hepatic fat content but also causes polyploidy, polynuclearization, dysplasia, cell death, and liver damage. Together, these studies suggest that liver tissue with short telomers are highly susceptible to fructose and respond with p53 activation and liver damage that is further exacerbated when p53 is lost resulting in dysplastic changes. |
| first_indexed | 2024-03-10T10:19:57Z |
| format | Article |
| id | doaj.art-dc6dcf87ffb24163bcfa81b13a96d793 |
| institution | Directory Open Access Journal |
| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-10T10:19:57Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Metabolites |
| spelling | doaj.art-dc6dcf87ffb24163bcfa81b13a96d7932023-11-22T00:30:31ZengMDPI AGMetabolites2218-19892021-06-0111639410.3390/metabo11060394Fructose Causes Liver Damage, Polyploidy, and Dysplasia in the Setting of Short Telomeres and p53 LossChristopher Chronowski0Viktor Akhanov1Doug Chan2Andre Catic3Milton Finegold4Ergün Sahin5Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USAHuffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USADepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USAHuffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USADepartment of Pathology, Baylor College of Medicine, Houston, TX 77030, USAHuffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USAStudies in humans and model systems have established an important role of short telomeres in predisposing to liver fibrosis through pathways that are incompletely understood. Recent studies have shown that telomere dysfunction impairs cellular metabolism, but whether and how these metabolic alterations contribute to liver fibrosis is not well understood. Here, we investigated whether short telomeres change the hepatic response to metabolic stress induced by fructose, a sugar that is highly implicated in non-alcoholic fatty liver disease. We find that telomere shortening in telomerase knockout mice (TKO) imparts a pronounced susceptibility to fructose as reflected in the activation of p53, increased apoptosis, and senescence, despite lower hepatic fat accumulation in TKO mice compared to wild type mice with long telomeres. The decreased fat accumulation in TKO is mediated by p53 and deletion of p53 normalizes hepatic fat content but also causes polyploidy, polynuclearization, dysplasia, cell death, and liver damage. Together, these studies suggest that liver tissue with short telomers are highly susceptible to fructose and respond with p53 activation and liver damage that is further exacerbated when p53 is lost resulting in dysplastic changes.https://www.mdpi.com/2218-1989/11/6/394telomeresliver fibrosisp53fructosetriglyceride |
| spellingShingle | Christopher Chronowski Viktor Akhanov Doug Chan Andre Catic Milton Finegold Ergün Sahin Fructose Causes Liver Damage, Polyploidy, and Dysplasia in the Setting of Short Telomeres and p53 Loss Metabolites telomeres liver fibrosis p53 fructose triglyceride |
| title | Fructose Causes Liver Damage, Polyploidy, and Dysplasia in the Setting of Short Telomeres and p53 Loss |
| title_full | Fructose Causes Liver Damage, Polyploidy, and Dysplasia in the Setting of Short Telomeres and p53 Loss |
| title_fullStr | Fructose Causes Liver Damage, Polyploidy, and Dysplasia in the Setting of Short Telomeres and p53 Loss |
| title_full_unstemmed | Fructose Causes Liver Damage, Polyploidy, and Dysplasia in the Setting of Short Telomeres and p53 Loss |
| title_short | Fructose Causes Liver Damage, Polyploidy, and Dysplasia in the Setting of Short Telomeres and p53 Loss |
| title_sort | fructose causes liver damage polyploidy and dysplasia in the setting of short telomeres and p53 loss |
| topic | telomeres liver fibrosis p53 fructose triglyceride |
| url | https://www.mdpi.com/2218-1989/11/6/394 |
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