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| Status |
Public on May 15, 2024 |
| Title |
PKD1 mutant clones within cirrhotic livers inhibit steatohepatitis without promoting cancer [Western Diet + CCl4] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Somatic mutations in non-malignant tissues are selected for because they confer increased clonal fitness, however, it is uncertain if these clones can benefit organ health. Here, ultra-deep targeted sequencing of 150 liver samples from 30 chronic liver disease patients revealed recurrent somatic mutations. PKD1 mutations were observed in 30% of patients, whereas they were only detected in 1.3% of hepatocellular carcinomas (HCCs). To interrogate tumor suppressor functionality, we perturbed PKD1 in two HCC cell lines and six in vivo models, in some cases showing that PKD1 loss protected against HCC, but in most cases showing no impact. However, Pkd1 haploinsufficiency accelerated regeneration after partial hepatectomy. We tested Pkd1 in fatty liver disease, showing that Pkd1 loss was protective against steatosis and glucose intolerance. Mechanistically, Pkd1 loss selectively increased mTOR signaling without SREBP activation. In summary, PKD1 mutations in cirrhotic livers exert adaptive functionality without increasing transformation risk.
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| Overall design |
Pkd1 WT, Het, and Homo litternate mice on "Western Diet + CCl4"NASH model for 3 months
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| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
Apr 21, 2024 |
| Last update date |
May 15, 2024 |
| Contact name |
Hao Zhu |
| E-mail(s) |
Hao.Zhu@utsouthwestern.edu
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| Organization name |
University of Texas Southwestern Medical Center
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| Department |
Children’s Research Institute
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| Street address |
6000 Harry Hines Blvd.
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| City |
Dallas |
| State/province |
TX |
| ZIP/Postal code |
75235 |
| Country |
USA |
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| Platforms (1) |
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| Samples (19)
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| Relations |
| BioProject |
PRJNA1102894 |
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