The ULK1-NCOA3 axis restrains de novo lipogenesis and prevents diet-induced steatohepatitis and fibrosis in mice

Year: 2026

Type: article

Abstract: Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are leading causes of cirrhosis and hepatocellular carcinoma. Defects in autophagy contribute to the development of MASLD; however, the role of 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 promotes, unexpectedly, 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.

Source: Journal of Clinical Investigation

DOI: 10.1172/jci191101

Institutions: University of California, Los Angeles, UCLA Health, Fraternal Order of Eagles, University of Iowa, Florida International University, Johns Hopkins University, VA Greater Los Angeles Healthcare System, Vanderbilt University

Language: English

Topic: Liver Disease Diagnosis and Treatment

Subfield: Epidemiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $5,200

Funders: National Science Foundation, American Heart Association, James B. Pendleton Charitable Trust, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, National Institute of Diabetes and Digestive and Kidney Diseases, UCLA AIDS Institute

Awards: A Heart-Liver-Adipose Axis: the role of inter-organ crosstalk in cardiometabolic risk., The role of the integrated stress response in brown adipose tissue-mediated metabolic adaptations, Graduate Research Fellowship Program (GRFP)

OpenAlex ID: W7148396689