Southern California Research Center for ALPD and Cirrhosis and Department of Pathology, University of Southern California, Los Angeles, CA 91011, USA
Progression of alcoholic liver disease (ALD) manifests itself with hepatocellular cell death, inflammation, hepatic stellate cell (HSC)-mediated perisinusoidal or pericellular fibrosis, the generation of CD133+ tumor-initiating stem cell-like cells (TICs), and liver tumorigenesis. Our center-supported research reveals that cell fate regulations necessary for these pathologic entities are causally associated with cell-type specific metabolic reprogramming. Increased iron accumulation in hepatic macrophages drives NF-κB-dependent M1 activation. Fatty acid desaturation is a prominent feature and essential for liver fibrosis and carcinogenesis via its novel link to a common morphogen pathway in HSCs and TICs. Cholesterol metabolism is also likely linked to HSC activation and TIC chemoresistance. We propose these metabolic mechanisms mediate the well-known association of inflammation, cirrhosis and liver cancer. Molecular mechanisms underlying these novel regulations will be discussed in this presentation.