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Published on: October 21, 2017
PKD1 mutant clones within cirrhotic livers inhibit steatohepatitis without promoting cancer
Min Zhu1, Yunguan Wang2, Tianshi Lu3
1Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, Children's Research Institute Mouse Genome Engineering Core, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Abstract:
Somatic mutations in non-malignant tissues are selected for because they confer increased clonal fitness. However, it is uncertain whether 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-1c activation. In summary, PKD1 mutations exert adaptive functionality on the organ level without increasing transformation risk.
Insights
Somatic mutations in the PKD1 gene can benefit liver health by protecting against fatty liver disease and improving regeneration. These mutations provide adaptive functionality without increasing cancer risk.
Area of Science:
- Genetics
- Hepatology
- Oncology
Background:
- Somatic mutations in non-malignant tissues are selected for increased clonal fitness.
- The role of these mutations in benefiting organ health remains unclear.
Purpose of the Study:
- To investigate the functional impact of somatic mutations, specifically in the PKD1 gene, on liver health and hepatocellular carcinoma (HCC) development.
- To determine if PKD1 mutations confer adaptive functionality at the organ level without increasing transformation risk.
Main Methods:
- Ultra-deep targeted sequencing of 150 liver samples from 30 chronic liver disease patients.
- Perturbation of PKD1 in HCC cell lines and in vivo models.
- Assessment of Pkd1's role in liver regeneration, fatty liver disease, steatosis, and glucose intolerance.
Main Results:
- Recurrent somatic mutations were identified, with PKD1 mutations found in 30% of patients.
- PKD1 loss showed mixed effects on HCC protection but accelerated liver regeneration.
- Pkd1 loss protected against steatosis and glucose intolerance in fatty liver disease models.
- Mechanistically, Pkd1 loss increased mTOR signaling without SREBP-1c activation.
Conclusions:
- Somatic PKD1 mutations can exert adaptive functionality at the organ level, promoting liver regeneration and protecting against metabolic dysfunction.
- These findings suggest that PKD1 mutations provide benefits to organ health without necessarily increasing the risk of hepatocellular carcinoma.
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