Journal article
The ULK1-NCOA3 axis restrains de novo lipogenesis and prevents diet-induced steatohepatitis and fibrosis in mice
The Journal of clinical investigation, Vol.136(11), e191101
06/01/2026
DOI: 10.1172/JCI191101
PMCID: PMC13221236
PMID: 41926189
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are leading causes of cirrhosis and hepatocellular carcinoma. Defects in autophagy contribute to the development of MASLD, however, the role of the Unc-51-like autophagy-activating kinase 1 (ULK1) in the pathophysiology of MASLD remains unclear. Herein, we show that ULK1, a serine/threonine kinase and core autophagy protein, is significantly repressed in human MASH livers, and that hepatocyte-specific loss of ULK1, unexpectedly, promotes hepatic steatosis and progression to liver fibrosis, without affecting basal autophagy flux. Phospho-proteomics identified the transcriptional coactivator NCOA3 as a downstream phospho-target of ULK1. Mechanistically, ULK1 phosphorylates NCOA3 to repress its transcriptional activity and restrain the CREB/CBP-mediated de novo lipogenic program. Accordingly, a phosphorylation-deficient NCOA3 mutant drives CREB/CBP-mediated lipogenesis, whereas genetic or pharmacological NCOA3 inhibition prevents steatosis, hepatic inflammation, and profibrotic signaling. Hence, ULK1-mediated NCOA3 phosphorylation is a fundamental and druggable checkpoint against the entire MASLD spectrum.
Details
- Title: Subtitle
- The ULK1-NCOA3 axis restrains de novo lipogenesis and prevents diet-induced steatohepatitis and fibrosis in mice
- Creators
- Young Do Koo - University of California, Los AngelesRomilia Tatiana Castillo - Fraternal Order of EaglesAsha Sukumaran Nair - Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, United States of AmericaMichael Garneau - Fraternal Order of EaglesChad Gochee - Fraternal Order of EaglesZachary V Campbell - Fraternal Order of EaglesTashya Shreyas Vakil - University of California, Los AngelesJua Ha - University of California, Los AngelesAlex Marti - University of IowaJamie Soto - University of IowaDebajyoti Das - University of California, Los AngelesNuria Martinez-Lopez - University of California, Los AngelesShipra Sharma - University of California, Los AngelesYennifer Delgado - University of California, Los AngelesCallie Phung - University of California, Los AngelesImmy A Ashley - University of California, Los AngelesEdmund D Kapelczak - University of California, Los AngelesRashel Jacobo - University of California, Los AngelesEric T Weatherford - University of IowaDao-Fu Dai - Johns Hopkins University School of MedicineJihane N Benhammou - University of California, Los AngelesAndrea G Marshall - Vanderbilt UniversityAntentor Hinton Jr - Vanderbilt UniversityLing Yang - University of IowaRenata O Pereira - Fraternal Order of EaglesTara TeSlaa - University of California, Los AngelesMehdi Bouhaddou - University of California, Los AngelesRajat Singh - University of California, Los AngelesE Dale Abel - University of California, Los Angeles
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.136(11), e191101
- DOI
- 10.1172/JCI191101
- PMID
- 41926189
- PMCID
- PMC13221236
- NLM abbreviation
- J Clin Invest
- ISSN
- 1558-8238
- eISSN
- 1558-8238
- Publisher
- American Society for Clinical Investigation
- Language
- English
- Electronic publication date
- 04/02/2026
- Date published
- 06/01/2026
- Academic Unit
- Molecular Physiology and Biophysics; Anatomy and Cell Biology; Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9985149579002771
Metrics
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