PKD1 mutant clones within cirrhotic livers inhibit steatohepatitis without promoting cancer.

Cell Metab

Children'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. Electronic address:

Published: August 2024

AI Article Synopsis

  • Scientists studied liver samples from patients with chronic liver disease and found many had mutations in a gene called PKD1.
  • These mutations seemed to help the liver stay healthy and recover faster after injury, but didn’t seem to help with cancer.
  • Overall, losing PKD1 might be good for liver health but does not make the liver more likely to turn into cancer.

Article 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.

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Source
http://dx.doi.org/10.1016/j.cmet.2024.05.015DOI Listing

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