A novel cystine based antioxidant attenuates oxidative stress and hepatic steatosis in diet-induced obese mice

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver pathologies and is associated with obesity and the metabolic syndrome. Here, we investigated the molecular mechanisms by which a novel cystine based glutathione precursor with added selenomethionine (F1) prevents hepatic steatosis in a moderate high fat dietary model of NAFLD. Adult (8 weeks old), male apolipoprotein E (ApoE)−/− mice were fed with a normal diet (ND) or high fat diet (HFD), consisting of 21% fat and 0.21% cholesterol, with or without dietary supplementation of F1 (3 g/kg food) for 16 weeks. Compared with ApoE−/− mice fed with ND with or without F1, ApoE−/− mice fed with HFD exhibited significant weight gain, hepatomegaly, and increased serum cholesterol and triglycerides levels with no change in serum albumin levels. High resolution light and electron microscopy revealed micro-and macro-vesicular steatosis in ApoE−/− mice fed on a HFD. HFD- induced obesity also led to increased lipogenesis, oxidative stress, activation of c-Jun-NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), perturbation of the BAX/BCL-2 rheostat, hepatocyte apoptosis, and activation of caspases 9 and 3. F1 fully prevented the adverse effects of HFD on serum triglyceride levels, body and liver weights, and hepatic steatosis and substantially attenuated HFD-induced increase in lipogenesis, oxidative stress, kinase activation, apoptotic signaling, and hepatocyte ultrastructural abnormalities. These results demonstrate that administration of F1, a glutathione precursor, ameliorates HFD-induced hepatic steatosis in ApoE−/− mice and emphasizes the role of oxidative stress in diet-induced obesity and hepatic steatosis.

The modulation of hepatic adenosine triphosphate and inflammation by eicosapentaenoic acid during severe fibrotic progression in the SHRSP5/Dmcr rat model

“…Abbreviations: MAPK, mitogen-activated protein kinase; ERK1/2, extracellular signal-regulated kinase 1/2; phospho-ERK1/2, phosphorylated ERK1/2; JNK, c-Jun amino-terminal kinases; phospho-JNK, phosphorylated JNK. (Schattenberg et al, 2006) and to be critically involved in a high fat dietary model of obesity-associated NAFLD (Sinha-Hikim et al, 2011). Conversely, we did not observe the activation of ERK1/2, JNK or p38 by the HFC diet or their inhibition by EPA in our study.…”

DKK3 expression in hepatocytes defines susceptibility to liver steatosis and obesity

“…Concordantly, we found that the MAPK cascades were activated in response to HFD stimulation; however, only JNK1/2 and p38, not ERK1/2 or MEK1/2, were regulated by DKK3. It has been established that the JNK pathway is closely associated with insulin resistance and that the p38 MAPK signaling pathway is involved in cellular inflammatory responses [37,38]. Our results indicated that DKK3 overexpression in HFD induced or genetic obese mice exhibited enhanced insulin sensitivity but reduced levels of proinflammatory cytokines.…”

Nicotine plus a high-fat diet triggers cardiomyocyte apoptosis

“…Only nuclei intersected by inclusion edges (upper and right borders) and within the frame were counted. The rate of CM apoptosis was expressed as the percentage of the TUNEL-positive apoptotic nuclei per total nuclei (apoptotic plus non-apoptotic) present within the reference area (Sinha-Hikim et al 2011a, 2011b). …”