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

Autor:	Zhu M; 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., Wang Y; Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229, USA., Lu T; Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Guo J; 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., Li L; 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., Hsieh MH; 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., Gopal P; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Han Y; Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Fujiwara N; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Wallace DP; The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS 66160, USA., Yu ASL; The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS 66160, USA., Fang X; 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., Ransom C; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Verschleisser S; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Hsiehchen D; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Hoshida Y; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Singal AG; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Yopp A; Department of Surgery, Division of Surgical Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Wang T; Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Zhu H; 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: hao.zhu@utsouthwestern.edu.
Jazyk:	angličtina
Zdroj:	Cell metabolism [Cell Metab] 2024 Aug 06; Vol. 36 (8), pp. 1711-1725.e8. Date of Electronic Publication: 2024 Jun 19.
DOI:	10.1016/j.cmet.2024.05.015
Abstrakt:	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. Competing Interests: Declaration of interests H.Z. is an academic co-founder of Quotient Therapeutics and Jumble Therapeutics, has sponsored research agreements with Alnylam Pharmaceuticals and Chroma Medicines, and serves on the scientific advisory boards of Newlimit and Ubiquitix. A.S.L.Y. has served as a consultant or advisory board member for Regulus, Calico, Otsuka, Navitor, Palladio, and Reata. A.G.S. serves as a consultant for Verve Therapeutics. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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