Rosiglitazone attenuates age- and diet-associated nonalcoholic steatohepatitis in male low-density lipoprotein receptor knockout mice

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) 2/2 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 2/2 mice. Although expression of genes mediating fatty acid oxidation and antioxidant responses were up-regulated in young LDLR 2/2 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 (PPARc) ligand, rosiglitazone. In addition to expected improvements in MS, newly identified mechanisms of PPARc ligand effects included stimulation of antioxidant gene expression and mitochondrial b-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 PPARc activation, which enhances b-oxidation. (HEPATOLOGY 2010;52:2001-2011 N onalcoholic steatohepatitis (NASH) is the most common liver disease in the Western world, affecting more than 18% of obese individuals.1 NASH is strongly associated with insulin resistance, and nearly five out of six NASH patients have metabolic syndrome (MS).2 NASH can progress to cirrhosis, but despite its severity and prevalence, there are no approved treatments for NASH. However, the recent PIVENS trial 3 demonstrated improvement in NASH histology with either vitamin E or the insulin-sensitizing peroxisome proliferator-activated receptor-gamma (PPARc) ligand, pioglitazone (PIO). The vitamin E effect underscored the critical role of oxidative stress in NASH but occurred in the absence of an Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPT1A, carnitine palmitoyltransferase 1a; DNL, de novo lipogenesis; HFD, high-fat diet; LCM, laser capture microdissection; LDLR, low-density lipoprotein receptor; MS, metabolic syndrome; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohep...

Western diet in ApoE-LDLR double-deficient mouse model of atherosclerosis leads to hepatic steatosis, fibrosis, and tumorigenesis

“…22,23 LDLR or ApoE single-knockout mice developed some of the NAFLD characteristics [24][25][26] but generally failed to broadly reflect the whole spectrum of NAFLD key features. As such, ApoE À / À mice on a fat-and cholesterol-enriched diet developed hepatic inflammation but only mild steatosis.…”

Alpha-lipoic acid attenuates insulin resistance and improves glucose metabolism in high fat diet-fed mice

“…Histological and biochemical analysis Paraffin-embedded liver sections were stained with periodic acid-Schiff, hematoxylin and eosin. The assessment of NAFLD was previously described [19] . The serum insulin level was measured using a mouse ELISA kit (CUSABIO) according to the manufacturer's instructions.…”

Nifedipine prevents hepatic fibrosis in a non-alcoholic steatohepatitis model induced by an L-methionine-and choline-deficient diet

“…However, there are very limited options to prevent NASH and NAFLD at this point. One potential group of drugs, the PPARγ ligands, such as rosiglitazone and pioglitazone, is reported to prevent NASH in animal models and in human patients (9,10,15). PPARγ ligands decrease steatosis through the inhibition of the activation of inflammatory and fibrotic genes, probably due to a decrease in oxidative stress.…”

“…Recently, the PIVENS trial demonstrated an improvement in NASH histology with either vitamin E or an insulin-sensitizing peroxisome proliferator-activated receptor-γ (PPARγ) ligand (9). Consistently, rosiglitazone was also found to attenuate the histological findings and decreased elevated serum enzyme levels in a NASH mouse model (10). In addition, a PPARα agonist, bezafibrate, is known to prevent NASH in animal models (11).…”