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<p>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 <i>Hsd17b13</i> and <i>Fasn</i>. 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 <i>HSD17B13</i>. We conclude novel mechanisms underlying ALD leading to spatially distinct establishment of hepatic steatosis and provide insight into disease pathogenesis.</p>

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Single cell multiomic landscape reveals gene programs driving lipid droplet heterogeneity in hepatic steatosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月23日

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  • Tejasav S. Sehrawat,
  • Shawna A. Cooper,
  • Amaia Navarro-Corcuera,
  • Ryan J. Schulze,
  • Mengfei Liu,
  • Usman Yaqoob,
  • Yubin Yeon,
  • Sangwoong Yoon,
  • Yung-Kyun Noh,
  • Chady Meroueh,
  • Joseph C. Ahn,
  • Josepmaria Argemi,
  • Ramon A. Bataller,
  • Mark A. McNiven,
  • Mrunal K. Dehankar,
  • Ying Li,
  • Jeong-Heon Lee,
  • Carol A. Casey,
  • William A. Faubion,
  • Tamas Ordog,
  • Patrick S. Kamath,
  • Douglas A. Simonetto,
  • Harmeet Malhi,
  • Sheng Cao,
  • Vijay H. Shah

摘要

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.