Single cell multiomic landscape reveals gene programs driving lipid droplet heterogeneity in hepatic steatosis
Alcohol-associated liver disease (ALD) in its earliest form is evidenced as hepatic steatosis which may progress to liver cirrhosis. The mechanisms behind this are poorly understood and therapeutics limited. Liver is a specialized organ exhibiting heterogeneity along the porto-central axis. Periportal preponderance of lipid droplet accumulation was noted in human ALD livers compared to other causes of hepatic steatosis. Using single cell multiomics, we studied transcriptional mechanisms across the hepatic lobule that could account for zonation of lipid droplets in a murine ALD model. Alcohol led to periportal zonation of lipogenesis-associated genes in mice, including Hsd17b13 and Fasn. Chromatin landscape studies demonstrated zonation of master transcription factors that led to these changes in the transcriptome. We utilized these data to provide novel insight into zone-specific HNF4α and PPARα regulation of HSD17B13. We conclude novel mechanisms underlying ALD leading to spatially distinct establishment of hepatic steatosis and provide insight into disease pathogenesis.
Authors
- Harmeet Malhi (ORCID: https://orcid.org/0000-0002-0882-4990)
- Patrick S. Kamath (ORCID: https://orcid.org/0000-0002-7888-1165)
- Yubin Yeon
- Tamás Ördög (ORCID: https://orcid.org/0000-0002-3940-7284)
- Usman Yaqoob (ORCID: https://orcid.org/0000-0003-0776-2828)
- Tejasav S. Sehrawat (ORCID: https://orcid.org/0000-0001-7346-5683)
- Mrunal Dehankar (ORCID: https://orcid.org/0000-0002-5953-9495)
- Mengfei Liu (ORCID: https://orcid.org/0000-0001-7156-5082)
- Carol A. Casey
- Sheng Cao
- Jeong-Heon Lee
- Joseph C. Ahn
- William A. Faubion
- Amaia Navarro-Corcuera
- Chady Meroueh
- Josepmaria Argemi
- Yung-Kyun Noh
- Douglas A. Simonetto
- Shawna A. Cooper
- Sangwoong Yoon
- Vijay H. Shah
- Ying Li
- Ramon A. Bataller
- Mark A. McNiven
Institutions
- Korea Institute for Advanced Study (KR)
- Mayo Clinic (US)
- University of Pittsburgh (US)
- Yale University (US)
- Centro de Investigación Biomédica en Red (ES)
- Mayo Clinic in Arizona (US)
- Mayo Clinic in Florida (US)
- University College London (GB)
- Hanyang University (KR)
- University of Nebraska Medical Center (US)
Publication Details
- Journal
- Scientific Reports
- Published
- 2026-02-23
- DOI
- https://doi.org/10.1038/s41598-026-39913-6
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Harvard University
- Ministry of Science and ICT, South Korea
- National Institutes of Health
- Center for Cell Signaling in Gastroenterology, Mayo Clinic