Recently, nonalcoholic steatohepatitis (NASH) was found to be correlated with cardiovascular disease events independently of the metabolic syndrome. The aim of this study was to investigate whether an atherogenic (Ath) diet induces the pathology of steatohepatitis necessary for the diagnosis of human NASH and how cholesterol and triglyceride alter the hepatic gene expression profiles responsible for oxidative stress. We

Running title: oxidative stress induced by high-fat diet Key words: insulin resistance, oxidative stress, β-oxidation, NADPH oxidase Reprint requests to corresponding author. 1The abbreviations used are the following: HFD, high-fat diet; ROS, reactive oxygen species; PPARα, peroxisome proliferator-activated receptor-α; Nox, NADPH oxidase; FFAs, free fatty acids; Acox, acyl-CoA oxidase; CPT-1a, carnitine palmitoyltransferase 1a; CYP2E1, cytochrome P450 2E1; GTT, glucose tolerance test; Gpx, glutathione peroxidase; ITT, insulin tolerance test. 2 AbstractInsulin resistance is a key pathophysiological feature of metabolic syndrome. However, the initial events triggering the development of insulin resistance and its causal relations with dysregulation of glucose and fatty acids metabolism remain unclear. We investigated biological pathways that have the potential to induce insulin resistance in mice fed a high-fat diet (HFD). We demonstrate that the pathways for reactive oxygen species (ROS) production and oxidative stress are coordinately up-regulated in both the liver and adipose tissue of mice fed a HFD prior to the onset of insulin resistance through discrete mechanism. In the liver, a HFD up-regulated genes involved in sterol regulatory element binding protein-1c (SREBP-1c)-related fatty acid synthesis and peroxisome proliferator-activated receptor-α (PPARα)-related fatty acid oxidation. In the adipose tissue, however, the HFD down-regulated genes involved in fatty acid synthesis and up-regulated NADPH oxidase (Nox) complex. Furthermore, increased ROS production preceded the elevation of TNF-α and free fatty acids (FFAs) in the plasma and liver. ROS may be an initial key event triggering HFD-induced insulin resistance.

Three forms of PPARs are expressed in the heart. In animal models, PPARγ agonist treatment improves lipotoxic cardiomyopathy; however, PPARγ agonist treatment of humans is associated with peripheral edema and increased heart failure. To directly assess effects of increased PPARγ on heart function, we created transgenic mice expressing PPARγ1 in the heart via the cardiac α-myosin heavy chain (α-MHC) promoter. PPARγ1-transgenic mice had increased cardiac expression of fatty acid oxidation genes and increased lipoprotein triglyceride (TG) uptake. Unlike in cardiac PPARα-transgenic mice, heart glucose transporter 4 (GLUT4) mRNA expression and glucose uptake were not decreased. PPARγ1-transgenic mice developed a dilated cardiomyopathy associated with increased lipid and glycogen stores, distorted architecture of the mitochondrial inner matrix, and disrupted cristae. Thus, while PPARγ agonists appear to have multiple beneficial effects, their direct actions on the myocardium have the potential to lead to deterioration in heart function.

Methods GPI-LpL construct.A PCR-based strategy was used to ligate the DNA sequence encoding the last 37 amino acids of membrane decay accelerating factor (DAF) (9, 10) containing the GPI-anchoring sequence to a human LpL (hLpL) minigene (11) (see Figure 1a). This strategy required the elimination of the LpL termination codon

One of the most critical issues in prostate cancer clinic is emerging hormone-refractory prostate cancers (HRPCs) and their management. Prostate cancer is usually androgen dependent and responds well to androgen ablation therapy. However, at a certain stage, they eventually acquire androgenindependent and more aggressive phenotype and show poor response to any anticancer therapies. To characterize the molecular features of clinical HRPCs, we analyzed gene expression profiles of 25 clinical HRPCs and 10 hormonesensitive prostate cancers (HSPCs) by genome-wide cDNA microarrays combining with laser microbeam microdissection. An unsupervised hierarchical clustering analysis clearly distinguished expression patterns of HRPC cells from those of HSPC cells. In addition, primary and metastatic HRPCs from three patients were closely clustered regardless of metastatic organs. A supervised analysis and permutation test identified 36 up-regulated genes and 70 down-regulated genes in HRPCs compared with HSPCs (average fold difference > 1.5; P < 0.0001). We observed overexpression of AR, ANLN, and SNRPE and down-regulation of NR4A1, CYP27A1, and HLA-A antigen in HRPC progression. AR overexpression is likely to play a central role of hormone-refractory phenotype, and other genes we identified were considered to be related to more aggressive phenotype of clinical HRPCs, and in fact, knockdown of these overexpressing genes by small interfering RNA resulted in drastic attenuation of prostate cancer cell viability. Our microarray analysis of HRPC cells should provide useful information to understand the molecular mechanism of HRPC progression and to identify molecular targets for development of HRPC treatment. [Cancer Res 2007;67(11):5117-25]

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Methods GPI-LpL construct.A PCR-based strategy was used to ligate the DNA sequence encoding the last 37 amino acids of membrane decay accelerating factor (DAF) (9, 10) containing the GPI-anchoring sequence to a human LpL (hLpL) minigene (11) (see Figure 1a). This strategy required the elimination of the LpL termination codon