Submission Date: Nov 10, 2022

Summary: Background and Aims: During severe or chronic hepatic injury, biliary epithelial cells (BECs), also known as cholangiocytes, undergo rapid reprogramming and proliferation, a process known as ductular reaction (DR), and allow liver regeneration by differentiating into both functional cholangiocytes and hepatocytes. While DR is a hallmark of chronic liver diseases, including advanced stages of non-alcoholic fatty liver disease (NAFLD), the early events underlying BEC activation are largely unknown. Since NAFLD initiates with increased lipid accumulation, a stage called steatosis; we hypothesized that BECs isolated directly from steatotic livers might address current knowledge gaps in early BEC activation.

Approach and Results: Here, we used methods allowing isolation and extensive transcriptional characterization of BECs from chow diet (CD)- and high-fat diet (HFD)-fed mice livers. We demonstrate that BECs readily accumulate lipids during HFD feeding and that lipid overload induces the conversion of adult cholangiocytes into active BECs through upregulation of the cell cycle and DNA replication signature. This event is accompanied by significant downregulation of extracellular matrix organization in BECs derived from HFD-fed mice livers but not CD-fed mice livers. Mechanistically, we found that lipid overload unleashes the activation of the E2F transcription factors in BECs, which drives cell cycle progression.

GEO Accession ID: GSE217739

PMID: 36876915