Date of Award
2025
Document Type
Dissertation
Degree Name
Pharmaceutical Sciences (Pharm.D.)
Department
Pharmaceutical Sciences
First Advisor
Sandra E. Reznik
Second Advisor
Jeanette C Perron
Third Advisor
Sabesan Yoganathan
Abstract
Metabolic associated Steatohepatitis (MASH) is characterized by lipid deposition, immune cell infiltration and fibrosis in the liver. MASH is a disease with a diverse etiology and has limited therapeutic approaches which includes weight loss, dietary modifications and the only FDA approved therapy, Resmetirom. Macrophage Inducible C Type Lectin (CLEC4E) receptor is expressed on hepatic macrophages and is increased in MASH patients. Animal models of MASH , obesity and cellular systems have shown that CLEC4E receptor may play a role in chronic tissue inflammation and fibrosis. This research project is focused on elucidating the effect of CLEC4E receptor on liver fibrosis using primary human derived cellular (in vitro) assay systems. Stimulating the monocyte derived macrophages with ligands trehalose-6’6-dibehenate (TDB) and βGlucosylceramide (βGlcCer) increased CLEC4E receptor expression and induced secretion of proinflammatory cytokine Macrophage inflammatory protein 1α (MIP1α). The expression of CLEC4E receptor is also increased in liver tissues of patients with fibrosis (Stage 3 and 4). Evaluation of the publicly available single cell datasets show that CLEC4E receptor is expressed in macrophages in hepatic tissue and this expression is increased in patients with liver injury. Further, lipotoxicity induced primary human hepatocytes also induced receptor expression in monocyte derived macrophages which confirms that CLEC4E receptor plays a role in sensing cellular damage from hepatocytes in disease. The effect of CLEC4E receptor stimulation on hepatic stellate cells which are key drivers of liver fibrosis was also evaluated. RNA-seq study of the hepatic stellate cells treated with TDB stimulated macrophages showed an upregulation of inflammatory genes and pathway. Epithelial to Mesenchymal transition pathway, myogenesis pathway and markers of hepatic stellate cells activation were downregulated. Thus, this research project has demonstrated that even though CLEC4E receptor is upregulated in MASH, it does not influence hepatic stellate cell activation directly using human derived cellular assay systems. Instead, macrophages with increased CLEC4E expression induce an inflammatory fibroblast-like phenotype and secretion of Senescent associated secretory protein IL6 in hepatic stellate cells. Thus, effect of modulating CLEC4E on hepatic macrophages on liver fibrosis progression and its potential as a therapeutic for MASH needs to further be evaluated.
Recommended Citation
Dave, Rajvee Manan, "ROLE OF MACROPHAGE INDUCIBLE C TYPE LECTIN (CLEC4E) RECEPTOR IN METABOLIC DYSFUNCTION ASSOCIATED STEATOHEPATITIS (MASH) AND LIVER FIBROSIS" (2025). Theses and Dissertations. 901.
https://scholar.stjohns.edu/theses_dissertations/901