The Epidemiology and Risk Factors of NASH

McCullough, Arthur J.

doi:10.1002/9780470987438.ch3

Cited by 82 publications

(107 citation statements)

References 148 publications

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“…Liver (80 mg) was homogenized in 400 l homogenization buffer (0.25 mM sucrose containing 1 mM Tris (Cl Ϫ ), pH 7.5, and 1 mM EDTA) with one stroke of a loose-fitting hand-driven all-glass homogenizer and mitochondria and peroxisomes were isolated from fresh liver homogenates as described by Crane et al 20 Oxidation of [1-14 C]fatty acids to watersoluble products was measured as described by Watkins et al 21 [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]lignoceric acid (C24:0), a very-long-chain fatty acid, and [1-14 C]palmitic acid (C16:0) were used to measure peroxisomal or mitochondrial fatty acid betaoxidation, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…1 NAFLD is likely the most frequent histological finding in patients with abnormal liver function tests in the western world. 2 Although the pathogenesis of NAFLD remains undefined, it is now well recognized that insulin resistance is usually present in almost all patients with NAFLD 3 and might be involved in the pathogenesis of this disease. 4,5 Because thiazolidinediones (TZD) are selective ligands of the peroxisome proliferator-activated receptor gamma (PPAR␥), 6 which acts as an insulin sensitizer, these drugs have been used in the treatment of patients with type 2 diabetes 7 and other insulin-resistant conditions, including NASH.…”

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confidence: 99%

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Effects of rosiglitazone on the liver histology and mitochondrial function in ob/ob mice†

et al. 2007

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Insulin resistance is present in almost all patients with nonalcoholic steatohepatitis (NAFLD), and mitochondrial dysfunction likely plays a critical role in the progression of fatty liver into nonalcoholic steatohepatitis. Rosiglitazone, a selective ligand of peroxisome proliferator-activated receptor gamma (PPAR␥), is an insulin sensitizer drug that has been used in a number of insulin-resistant conditions, including NAFLD. The aim of this study was to analyze the effects of rosiglitazone on the liver histology and mitochondrial function in a model of NAFLD. All studies were carried out in wild-type and leptin-deficient (ob/ob) C57BL/6J mice. Ob/ob mice were treated with 1 mg/kg/day, and activity of mitochondrial respiratory chain (MRC), beta-oxidation, lipid peroxidation, glutathione content in mitochondria, and 3-tyrosine-nitrated proteins in mitochondria were measured. In addition, histological and ultrastructural changes induced by rosiglitazone were also noted. Rosiglitazone treatment increased liver steatosis, particularly microvesicular steatosis. In these animals, mitochondria were markedly swollen with cristae peripherally placed. In ob/ob mice, this drug increased PPAR␥ protein expression and lipid peroxide content in liver tissue and decreased glutathione concentration in mitochondria. Rosiglitazone suppressed the activity of complex I of the MRC in ob/ob mice, but did not affect beta-oxidation. 3-Tyrosine nitrated mitochondrial proteins, significantly increased in ob/ob mice, were not modified by rosiglitazone treatment. Conclusion: Treatment of ob/ob mice with rosiglitazone did not reverse histological lesions of NAFLD or improve MRC activity. On the contrary, rosiglitazone reduced activity of complex I and increased oxidative stress and liver steatosis.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Effects of rosiglitazone on the liver histology and mitochondrial function in ob/ob mice†

et al. 2007

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“…Accumulating evidence suggests that NASH is potentially progressive, whereas simple steatosis (SS), indicated by liver biopsies, follows a more benign course with little or no progression. 1,3,4 Therefore, it is important to identify the biological pathways that underlie the pathogenesis of NASH and distinguish it from SS.…”

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confidence: 99%

A systems biology approach to the pathogenesis of obesity-related nonalcoholic fatty liver disease using reverse phase protein microarrays for multiplexed cell signaling analysis

et al. 2007

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Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease. Omental adipose tissue, a biologically active organ secreting adipokines and cytokines, may play a role in the development of NAFLD. We tested this hypothesis with reverse-phase protein microarrays (RPA) for multiplexed cell signaling analysis of adipose tissue from patients with NAFLD. Omental adipose tissue was obtained from 99 obese patients. Liver biopsies obtained at the time of surgery were all read by the same hepatopathologist. Adipose tissue was exposed to rapid pressure cycles to extract protein lysates. RPA was used to investigate intracellular signaling. Analysis of 54 different kinase substrates and cell signaling endpoints showed that an insulin signaling pathway is deranged in different locations in NAFLD patients. Furthermore, components of insulin receptor-mediated signaling differentiate most of the conditions on the NAFLD spectrum. For example, PKA (protein kinase A) and AKT/mTOR (protein kinase B/mammalian target of rapamycin) pathway derangement accurately discriminates patients with NASH from those with the non-progressive forms of NAFLD. PKC (protein kinase C) delta, AKT, and SHC phosphorylation changes occur in patients with simple steatosis. Amounts of the FKHR (forkhead factor Foxo1)phosphorylated at S256 residue were significantly correlated with AST/ALT ratio in all morbidly obese patients. Furthermore, amounts of cleaved caspase 9 and pp90RSK S380 were positively correlated in patients with NASH. Specific insulin pathway signaling events are altered in the adipose tissue of patients with NASH compared with patients with nonprogressive forms of NAFLD. Conclusion: These findings provide evidence for the role of omental fat in the pathogenesis, and potentially, the progression of NAFLD. (HEPATOLOGY 2007;46:166-172.)

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“…In the larger Olmsted County Community Study (11), 2 of 420 NAFLD patients developed hepatocellular carcinoma during a 7-year follow-up period. The estimated rate of liver-related deaths over 10 years was 12% for NASH patients (9,10).…”

Section: Nonalcoholic Steatohepatitis (Nash): Natural History and Insmentioning

confidence: 99%

Life Style-Related Diseases of the Digestive System: Gene Expression in Nonalcoholic Steatohepatitis Patients and Treatment Strategies

et al. 2007

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Abstract. Nonalcoholic steatohepatitis (NASH) is a subset of nonalcoholic fatty liver disease (NAFLD) and sometimes progresses to cirrhosis and liver failure. We analyzed the expression profiles of approximately 50,000 genes and biological pathways in NASH patients in comparison with simple steatosis patients by using the analytical technique of GSEA (Gene Set Enrichment Analysis) by DNA microarrays. Although expressions of various genes were altered, GSEA showed clearly lower expression of nuclear receptors, including the peroxisome proliferatoractivated receptor gamma (PPARγ) pathway. In a preliminary study we therefore investigated the therapeutic effect of low-dose pioglitazone (15 mg / day per body for 24 weeks), a synthetic ligand for PPARγ, in 12 NASH patients. A decrease in aminotransferase (ALT) values to within the normal range was observed in 7 (58.3%) of the patients, and because the dose of pioglitazone was lower than that ordinarily used, no side effects, such as fatigue, lower extremity edema, or weight gain, were observed. In conclusion, the results confirmed involvement of the PPARγ pathway in NASH and the therapeutic utility of a PPARγ ligand.

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The Epidemiology and Risk Factors of NASH

Cited by 82 publications

References 148 publications

Effects of rosiglitazone on the liver histology and mitochondrial function in ob/ob mice†

Effects of rosiglitazone on the liver histology and mitochondrial function in ob/ob mice†

A systems biology approach to the pathogenesis of obesity-related nonalcoholic fatty liver disease using reverse phase protein microarrays for multiplexed cell signaling analysis

Life Style-Related Diseases of the Digestive System: Gene Expression in Nonalcoholic Steatohepatitis Patients and Treatment Strategies

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