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• W2022184946 abstract "Nonalcoholic fatty liver disease (NAFLD) is a common complication of obesity that can progress to nonalcoholic steatohepatitis (NASH), a serious liver pathology that can advance to cirrhosis. The mechanisms responsible for NAFLD progression to NASH remain unclear. Lack of a suitable animal model that faithfully recapitulates the pathophysiology of human NASH is a major obstacle in delineating mechanisms responsible for progression of NAFLD to NASH and, thus, development of better treatment strategies. We identified and characterized a novel mouse model, middle-aged male low-density lipoprotein receptor (LDLR)(-/-) mice fed a high-fat diet (HFD), which developed NASH associated with four of five metabolic syndrome (MS) components. In these mice, as observed in humans, liver steatosis and oxidative stress promoted NASH development. Aging exacerbated the HFD-induced NASH such that liver steatosis, inflammation, fibrosis, oxidative stress, and liver injury markers were greatly enhanced in middle-aged versus young LDLR(-/-) mice. Although expression of genes mediating fatty acid oxidation and antioxidant responses were up-regulated in young LDLR(-/-) mice fed HFD, they were drastically reduced in MS mice. However, similar to recent human trials, NASH was partially attenuated by an insulin-sensitizing peroxisome proliferator-activated receptor-gamma (PPARγ) ligand, rosiglitazone. In addition to expected improvements in MS, newly identified mechanisms of PPARγ ligand effects included stimulation of antioxidant gene expression and mitochondrial β-oxidation, and suppression of inflammation and fibrosis. LDLR-deficiency promoted NASH, because middle-aged C57BL/6 mice fed HFD did not develop severe inflammation and fibrosis, despite increased steatosis.MS mice represent an ideal model to investigate NASH in the context of MS, as commonly occurs in human disease, and NASH development can be substantially attenuated by PPARγ activation, which enhances β-oxidation." @default.
• W2022184946 created "2016-06-24" @default.
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• W2022184946 date "2010-10-11" @default.
• W2022184946 modified "2023-10-18" @default.
• W2022184946 title "Rosiglitazone attenuates age- and diet-associated nonalcoholic steatohepatitis in male low-density lipoprotein receptor knockout mice" @default.
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• W2022184946 doi "https://doi.org/10.1002/hep.23941" @default.
• W2022184946 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2991614" @default.
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