Sayed Obaidullah Aseem, MD, PhD

Pilot Research Award
$50,000 over one year

Virginia Commonwealth University

Lipidomic changes in Fibroinflammatory Signaling in Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is characterized by scarring of the bile ducts, termed biliary fibrosis. The pathogenesis of biliary fibrosis involves activation of cholangiocytes that line these ducts to stimulate the fibrosis producing myofibroblasts and inflammatory cells around the bile ducts. While some progress has been made in understanding how cholangiocytes are activated, the changes in their cellular lipid profile that allows their activation and subsequent signaling remains poorly investigated and poses a major barrier for developing effective therapies for biliary fibrosis. Our preliminary data point to multiple lipidomic changes, including reduction of cellular content of an essential fatty acid, linoleic acid, by the transforming growth factor-β (TGFβ) signaling, a key mediator of solid organ fibrosis. The reduction of linoleic acid is partially dependent on TGFβ-stimulated upregulation of a lipid modifying enzyme,

stearoyl-CoA desaturase-1 (SCD). Aramchol, an inhibitor of SCD, significantly reduces TGFβ activated fibroinflammatory signals in cholangiocytes and attenuates markers of biliary fibrosis in a PSC mouse model. Next, we propose to examine the role of TGFβ and SCD in producing a fibroinflammatory lipid profile in cholangiocytes in cell and mouse models of PSC. We also propose untargeted analysis of spatial lipid changes in PSC liver sections compared to control samples using a mass spectrometry technique, matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). This will allow us to identify regional differences in lipid profile, including the bile ducts of PSC. We will integrate this data with the transcriptome of these regions that determine additional signals and enzymes responsible for changes in the lipid profile. These integrative analyses will allow to comprehensively define the fibroinflammatory lipid signaling in the bile ducts of PSC, extensively broadening the understanding of pathogenesis of this disease.