Plasma oxCoQ9 correlated with fibrosis progression. The mechanism of fibrosis may involve fructose inducing ABT-263 order increased ROS associated with CD11b+F4/80+Gr1+ hepatic macrophage aggregation, resulting in transforming growth factor β1–signaled collagen deposition and histologically

visible hepatic fibrosis. (HEPATOLOGY 2010) Epidemiologic data suggest that there has been a significant rise in calories consumed from saturated fat and fructose-rich foods.1 This has been paralleled by an increasing prevalence of obesity and its associated hepatic comorbidity, nonalcoholic fatty liver disease (NAFLD).2 Natural history studies of NAFLD indicate that the presence of fibrosis within the more severe phenotype, nonalcoholic

steatohepatitis (NASH), is an important predictor of adverse long-term outcomes, including diabetes and progression to cirrhosis.3, 4 Fibrosis progression to cirrhosis is thought to be modulated through hepatic reactive oxygen species (ROS) generation, macrophage activation, and transforming growth factor β (TGF-β)-mediated collagen deposition.5-7 Although recent data have highlighted potential biomarkers for distinguishing NAFLD from NASH, liver biopsy continues to be the gold R428 in vivo standard for monitoring fibrosis progression in NASH.8 The role of saturated fat and fructose in triggering the mechanisms of fibrosis progression in NASH remain to be clearly elucidated.9 Our understanding of this process has been hampered by the lack of a comprehensive and physiologic small animal model of NASH with fibrosis. To date,

small animal models of NASH with fibrosis involve genetic manipulation,10-12 forced overfeeding,13 or contrived diets deficient in methionine and choline (MCD).14-17 Although each of these models has been check details valuable, they fail to address key aspects of the process in humans. For example, few humans have diets that are deficient in methionine and choline. Moreover, rodents exposed to methionine- and choline-deficient diets are not obese; rather, they lose weight and become more insulin-sensitive.17 Recent studies, particularly the ALIOS diet using ad libitum high-fructose and high–trans fat diets in small animals, have had some success in generating steatosis with inflammation but failed to produce significant fibrosis.18, 19 Lieber et al.20 fed a high-fat-liquid diet (71% kcal from fat) to rats ad libitum, but these animals only developed steatosis without any fibrosis or collagen deposition. Genetically modified mice (such as liver-specific phosphotase and tensin homolog–suppressed10 or carcinoembryonic antigen-related cell adhesion molecule–inactivated21) do produce fibrosis when metabolically challenged with high-fat diets, but nongenetically modified animals either take very long periods or require large animal models to generate NASH with fibrosis.