Abstract

In liver tissue, the cellular organization is highly specialized. The relationship and crosstalk between liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), and hepatocytes are well orchestrated in the sinusoidal niche. As the liver pericyte, HSCs are important for tissue health and play a key role in e.g., retinoid storage, sinusoidal blood flow, and metabolism. The development of obesity-related liver diseases like non-alcoholic steatohepatitis (NASH) changes the liver microenvironment and drives the transdifferentiation of HSCs into pro-fibrogenic myofibroblasts. This thesis investigated the role of HSCs in health and disease.

The work in this thesis is divided into two research papers. In Chapter II (paper I), we aimed to elucidate the function of HSC-expressed plasmalemma vesicle-associated protein (PLVAP) in adult mice. Here we created a new mouse model of conditional Plvap-deficiency and were able to establish a novel metabolic role of HSC-PLVAP during fasting. RNAsequencing experiments, lipidomics, imaging, and fatty acid tracing indicated reduced lipid metabolic handling as a consequence of Plvap ablation. Loss of PLVAP blunted pre-prandial hepatic fatty acid uptake and subsequently suppressed fatty acid oxidation and ketogenesis in hepatocytes. A conquest most likely caused by altered caveolae transport.

In Chapter III (paper II), we surveyed the spectrum of human non-alcoholic fatty liver disease (NAFLD). To study HSCs in human pathophysiology, we collected liver biopsies from severely obese patients enrolled for gastric bypass. We assessed disease-driven changes in HSC-secreted proteins by applying bulk RNA-sequencing. Using RNAsequencing and single-molecule fluorescent in situ hybridization, we identified secreted SMOC2 as a protein expressed by activated HSCs. The expression of SMOC2 increased with NAFLD severity and was detectable in blood plasma. We found that SMOC2 had a predictive AUROC accuracy of 0.88, rendering SMOC2 a potential new diagnostic noninvasive biomarker for human NASH. 

In summary, this work provides an increased understanding of the role of HSCs. By applying a genetic mouse model and examining human liver biopsies, we have shown that HSCs are vital for hepatic lipid handling during fasting and that activated human HSCs secrete SMOC2 protein, which can accurately discriminate NASH from no-NASH patients.
Original languageEnglish
Awarding Institution
  • University of Southern Denmark
Supervisors/Advisors
  • Ravnskjær, Kim, Principal supervisor
Date of defence17. Jan 2024
Publisher
DOIs
Publication statusPublished - 9. Jan 2024

Note re. dissertation

A print copy of the thesis can be accessed at the Library. 

Keywords

  • Hepatic Stellate Cells
  • Liver
  • Fatty Acids
  • Metabolism
  • NAFLD/NASH
  • PLVAP
  • SMOC2
  • Microvasculature

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