No abstract

Accumulation of cholesterol in the liver is associated with the development of non-alcoholic steatohepatitis-related fibrosis. However, underlying mechanisms are not well understood. The present study investigated the role of inducible nitric oxide synthase (iNOS) in cholesterol-induced liver fibrosis by feeding wild-type (WT) and iNOS-deficient mice with control or high-cholesterol diet (HCD) for 6 weeks. WT mice fed with HCD developed greater liver fibrosis, compared with iNOS-deficient mice, as evident by Sirius red staining and higher expression levels of profibrotic genes. Enhanced liver fibrosis in the presence of iNOS was associated with hypoxia-inducible factor-1a stabilization, matrix metalloproteinase-9 expression, and enhanced hepatic DNA damage. The profibrotic role of iNOS was also demonstrated in vivo using a selective inhibitor of iNOS as well as in vitro in a rat liver stellate cell line (HSC-T6). In conclusion, these findings suggest that iNOS is an important mediator in HCD-induced liver fibrosis.Laboratory Investigation (2015) 95, 914-924;

No abstract

Prolonged GTE supplementation dramatically increased hepatic oxidative stress, inflammation and liver injury, and altered the bile acid synthesis pathway in mice fed a HCD.

Nonalcoholic fatty liver diseases (NAFLD) is one of the most common chronic liver disease in Western countries. Oxygen is a central component of the cellular microenvironment, which participate in the regulation of cell survival, differentiation, functions and energy metabolism. Accordingly, sufficient oxygen supply is an important factor for tissue durability, mainly in highly metabolic tissues, such as the liver. Accumulating evidence from the past few decades provides strong support for the existence of interruptions in oxygen availability in fatty livers. This outcome may be the consequence of both, impaired systemic microcirculation and cellular membrane modifications which occur under steatotic conditions. This review summarizes current knowledge regarding the main factors which can affect oxygen supply in fatty liver.

No abstract

Accumulating evidence suggests that fatty livers are particularly more susceptible to several pathological conditions, including hepatic inflammation, cirrhosis and liver cancer. However the exact mechanism of such susceptibility is still largely obscure. The current study aimed to elucidate the effect of hepatocytes lipid accumulation on the nuclear electrophilic stress. Accumulation of intracellular lipids was significantly increased in HepG2 cells incubated with fatty acid (FA) complex (1 mM, 2:1 oleic and palmitic acids). In FA-treated cells, lipid droplets were localized around the nucleus and seemed to induce mechanical force, leading to the disruption of the nucleus morphology. Level of reactive oxygen species (ROS) was significantly increased in FA-loaded cells and was further augmented by treatment with moderate stressor (CoCl2). Increased ROS resulted in formation of reactive carbonyls (aldehydes and ketones, derived from lipid peroxidation) with a strong perinuclear accumulation. Mass-spectroscopy analysis indicated that lipid accumulation per-se can results in modification of nuclear protein by reactive lipid peroxidation products (oxoLPP). 235 Modified proteins involved in transcription regulation, splicing, protein synthesis and degradation, DNA repair and lipid metabolism were identified uniquely in FA-treated cells. These findings suggest that steatosis can affect nuclear redox state, and induce modifications of nuclear proteins by reactive oxoLPP accumulated in the perinuclear space upon FA-treatment.

Aims: The current study aim was to elucidate the antihypoglycemic role and mechanism of inducible nitric oxide synthase (iNOS) under inflammatory stress. Methods: Liver inflammatory stress was induced in wild-type (WT) and iNOS-knockout (iNOS -/ -) mice by lipopolysaccharide (LPS) (5 mg/kg) with and without the background of nonalcoholic steatohepatitis (NASH)-Induced by high cholesterol diet (HCD, 6 weeks). Results: HCD led to steatohepatitis in WT and iNOS -/ -mice. LPS administration caused marked liver inflammatory damage only in cholesterol-fed mice, which was further exacerbated in the absence of iNOS. Glucose homeostasis was significantly impaired and included fatal hypoglycemia and inhibition of glycogen decomposition. In iNOS -/ -hypoxia-inducible factor-1 (HIF1), signaling was impaired compared to control WT. Using hydrodynamic gene transfer method HIF1a was expressed in the livers of iNOS -/ -mice, and significantly ameliorated cholesterol and LPS-induced liver damage. WT mice overexpressing HIF1a exhibited higher blood glucose levels and lower glycogen contents after LPS injection. Conversely, induction of HIF1a was not effective in preventing LPSinduced glucose lowering effect in iNOS -/ -mice. The critical role of NO signaling in hepatocytes glucose output mediated by HIF1 pathway was also confirmed in vitro. Results also demonstrated increased oxidative stress and reduced heme oxygenase-1 mRNA in the livers of iNOS -/ -mice. Furthermore, the amounts of plasma tumor necrosis factor-a (TNFa) and intrahepatic TNFa mRNA were significantly elevated in the absence of iNOS. Innovation and Conclusion: These data highlight the essential role of iNOS in the glycemic response to LPS in NASH conditions and argues for the beneficial effects of iNOS.