PKD1 mutant clones within cirrhotic livers inhibit steatohepatitis without promoting cancer
Open accessAbstract
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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Some mutations found in cirrhotic livers induce liver regeneration without promoting cancer.
“Importantly, some of these mutations induce liver regeneration without promoting cancer (31, 32).”
From Somatic mutations in TBX3 promote hepatic clonal expansion by accelerating VLDL secretion (2025) · cites this paper as [32]
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- Authors
- Zhu, M., Wang, Y., Lu, T., Guo, J., Li, L., Hsieh, M.-H., Gopal, P., Han, Y., Fujiwara, N., Wallace, D. P., Yu, A. S. L., Fang, X., Ransom, C., Verschleisser, S., Hsiehchen, D., Hoshida, Y., Singal, A. G., Yopp, A., Wang, T., & Zhu, H.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Cincinnati Children's Hospital Medical Center (US)
- University of Kansas Medical Center (US)
- Corresponding author
- Zhu, Hao
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2024-08
- Volume
- 36
- Issue
- 8
- Pages
- 1711-1725.e8
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC12133308
- OpenAlex
- W4399831673
- Cited by
- 9
- References
- 40
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 2
- FWCI
- 2.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 370 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Funders
- University of Texas Southwestern Medical Center
- National Institutes of Health (SCR_017949, NIH U54, 1s10od032267-01)
- National Institute on Alcohol Abuse and Alcoholism (R01AA028791)
- National Cancer Institute (U01CA271887, R01CA258584, P30CA142543)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK125396, P30DK127984, U54DK126126)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- PKD1, somatic mutations, liver cirrhosis, steatohepatitis, hepatic steatosis, hepatocellular carcinoma, tumor suppressor function, clonal fitness, partial hepatectomy, liver regeneration, mTOR signaling, SREBP-1c, impaired glucose tolerance, steatosis, chronic liver disease
- MeSH terms
- Animals, Fatty Liver, Female, Carcinoma, Hepatocellular, Humans, Liver Cirrhosis, Liver Neoplasms, Male, Mice, Inbred C57BL, Mutation, Signal Transduction, Cell Line, Tumor, TRPP Cation Channels, Mice, TOR Serine-Threonine Kinases
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