Medicine and Health Sciences Commons^™

Differential Methylation Patterns In Lean And Obese Non-Alcoholic Steatohepatitis-Associated Hepatocellular Carcinoma, Emma Hymel, Kurt W. Fisher, Evi A. Farazi

Journal Articles: Epidemiology

BACKGROUND: Nonalcoholic fatty liver disease affects about 24% of the world's population and may progress to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). While more common in those that are obese, NASH-HCC can develop in lean individuals. The mechanisms by which HCC develops and the role of epigenetic changes in the context of obesity and normal weight are not well understood.

METHODS: In this study, we used previously generated mouse models of lean and obese HCC using a choline deficient/high trans-fat/fructose/cholesterol diet and a choline supplemented/high trans-fat/fructose/cholesterol diet, respectively, to evaluate methylation differences in HCC progression in lean versus …

Differential Progression Of Unhealthy Diet-Induced Hepatocellular Carcinoma In Obese And Non-Obese Mice, Emma Hymel, Elizabeth M. Vlock, Kurt W. Fisher, Paraskevi A. Farazi

Journal Articles: Epidemiology

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) ranks first among liver diseases in Western countries. NAFLD is typically associated with obesity and diabetes, however it also develops in lean individuals without metabolic syndrome. The prevalence of lean NAFLD is 7 percent in the U.S. and 25-30 percent in some Asian countries. NAFLD starts with excess liver fat accumulation (NAFL), progresses to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). The pathogenesis of lean NASH-HCC and how it differs from obese NASH-HCC is not well understood.

METHODS: In this work, we generated a mouse model of lean and obese NASH-HCC using a …

Death Receptor 5 Internalization Is Required For Lysosomal Permeabilization By Trail In Malignant Liver Cell Lines., Yuko Akazawa, Justin L. Mott, Steven F. Bronk, Nathan W. Werneburg, Alisan Kahraman, Maria Eugenia Guicciardi, Xue Wei Meng, Shigeru Kohno, Vijay H. Shah, Scott H. Kaufmann, Mark A. Mcniven, Gregory J. Gores

Journal Articles: Biochemistry & Molecular Biology

BACKGROUND & AIMS: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) cytotoxicity in hepatocellular carcinoma cells is mediated by lysosomal permeabilization. Our aims were to determine which TRAIL receptor, death receptor (DR) 4 or DR5, mediates lysosomal permeabilization and assess whether receptor endocytosis followed by trafficking to lysosomes contributes in this process.

METHODS: TRAIL ligand internalization in Huh-7 cells was examined by confocal microscopy using Flag-tagged TRAIL, whereas DR4- and DR5-enhanced green fluorescent protein internalization was assessed by total internal reflection microscopy. Clathrin-dependent endocytosis was inhibited by expressing dominant negative dynamin.

RESULTS: Although Huh-7 cells express both TRAIL receptors, short hairpin RNA …