PKD1 Mutant Clones Within Cirrhotic Livers Inhibit Steatohepatitis Without Promoting Cancer

Authors

Min Zhu
Yunguan Wang
Tianshi Lu
Jason Guo
Lin Li
Meng-Hsiung Hsieh
Purva Gopal
Yi Han
Naoto Fujiwara
Darren P Wallace
Alan S L Yu
Xiangyi Fang
Crystal Ransom
Sara Verschleisser
David Hsiehchen
Yujin Hoshida
Amit G Singal
Adam Yopp
Tao Wang
Hao Zhu

Publication Date

8-6-2024

Journal

Cell Metabolism

DOI

10.1016/j.cmet.2024.05.015

PMID

38901424

PMCID

PMC12133308

PubMedCentral® Posted Date

8-6-2025

PubMedCentral® Full Text Version

Author MSS

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.

Keywords

Humans, Liver Neoplasms, Animals, TRPP Cation Channels, Carcinoma, Hepatocellular, Mutation, Mice, Liver Cirrhosis, Fatty Liver, Male, TOR Serine-Threonine Kinases, Mice, Inbred C57BL, Cell Line, Tumor, Female, Signal Transduction, HCC, NASH, PKD1, fatty liver, liver cancer, mTOR, somatic mutations, steatosis

Published Open-Access

yes

Recommended Citation

Zhu, Min; Wang, Yunguan; Lu, Tianshi; et al., "PKD1 Mutant Clones Within Cirrhotic Livers Inhibit Steatohepatitis Without Promoting Cancer" (2024). Faculty, Staff and Student Publications. 6757.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6757