Rosiglitazone Attenuates Age- and Diet-Associated Nonalcoholic Steatohepatitis in Male Low-Density Lipoprotein Receptor Knockout Mice

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 (PPAR gamma) ligand, rosiglitazone In addition to expected improvements in MS, newly identified mechanisms of PPAR gamma ligand effects included stimulation of antioxidant gene expression and mitochondrial beta-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 Conclusion 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 PPAR gamma activation, which enhances beta-oxidation (HEPATOLOGY 2010,52 2001-2011)