Hepatic Steatosis In Humans Research Articles

High sensitivity of fatty liver Shionogi (FLS) mice to diethylnitrosamine hepatocarcinogenesis: Comparison to C3H and C57 mice

The fatty liver Shionogi (FLS) mouse is a new inbred strain that spontaneously develops fatty liver with infiltration of mononuclear cells. Moreover, this mouse is known to frequently develop spontaneous hepatic cancers. Recently, human non-alcholic steatohepatitis (NASH) has been focused of attention regarding hepatocellular carcinoma. Therefore, this mouse has potential as a model for human hepatic cancer due to steatosis. It is of interest therefore, whether it exhibits elevated susceptibility not only regarding spontaneous tumor development but also to chemical hepatocarcinogens. To examine this concern, we examined diethylnitrosamine (DEN) hepatocarcinogenesis in FLS mice with 30 ppm in drinking water for 26 weeks in comparison to two other strains of mice, C3H and C57. The induction of spontaneous and DEN-induced hepatic tumors was clearly increased in the FLS case, along with levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, as compared to the other strains, with or without DEN treatment. These results indicate that the oxidative DNA stress is intimately involved in hepatocarcinogenesis in FLS mice and provide further support for use of this mouse as a useful model for investigating hepatocarcinogenesis due to human hepatic steatosis.

Heme oxygenase-1 levels and oxidative stress-related parameters in non-alcoholic fatty liver disease patients

Non-alcoholic steatohepatitis (NASH) is a disorder that is histologically characterized by macrovesicular steatosis and lobular hepatitis with necrosis or ballooning degeneration and fibrosis. NASH can range from a benign condition to end-stage liver disease. The mechanisms promoting transition from steatosis to NASH appear to involve multiple cellular adaptations to the oxidative stress occurring when fatty acid metabolism is altered. We evaluated the relationship between lipid peroxidation and other oxidative stress biomarkers with changes in expression of heme oxygenase-1 (HO-1) in human hepatic steatosis ranging from simple steatosis to NASH. HO-1 expression, lipid peroxidation, ferritin and GSH levels were assayed from liver biopsies obtained from 60 subjects: 35 with NASH, 15 with simple steatosis and 10 controls. The HO-1 expression was significantly increased in NASH patients and the increase reflected the severity of the disease. A significant correlation was observed between the increased levels of HO-1 and ferritin, and between the increased levels of HO-1 and lipid peroxidation. Moreover, NASH patients with lower levels of GSH exhibited higher expression of HO-1. The induction of HO-1 is an adaptive response against oxidative damage elicited by lipid peroxidation and it may be critical in the progression of the disease.

Lipid peroxidation in hepatic steatosis in humans is associated with hepatic fibrosis and occurs predominately in acinar zone 3.

Hepatic steatosis has been shown to be associated with lipid peroxidation and hepatic fibrosis in a variety of liver diseases including non-alcoholic fatty liver disease. However, the lobular distribution of lipid peroxidation associated with hepatic steatosis, and the influence of hepatic iron stores on this are unknown. The aim of this study was to assess the distribution of lipid peroxidation in association with these factors, and the relationship of this to the fibrogenic cascade. Liver biopsies from 39 patients with varying degrees of hepatic steatosis were assessed for evidence of lipid peroxidation (malondialdehyde adducts), hepatic iron, inflammation, fibrosis, hepatic stellate cell activation (alpha-smooth muscle actin and TGF-beta expression) and collagen type I synthesis (procollagen alpha1 (I) mRNA). Lipid peroxidation occurred in and adjacent to fat-laden hepatocytes and was maximal in acinar zone 3. Fibrosis was associated with steatosis (P < 0.04), lipid peroxidation (P < 0.05) and hepatic iron stores (P < 0.02). Multivariate logistic regression analysis confirmed the association between steatosis and lipid peroxidation within zone 3 hepatocytes (P < 0.05), while for hepatic iron, lipid peroxidation was seen within sinusoidal cells (P < 0.05), particularly in zone 1 (P < 0.02). Steatosis was also associated with acinar inflammation (P < 0.005). alpha-Smooth muscle actin expression was present in association with both lipid peroxidation and fibrosis. Although the effects of steatosis and iron on lipid peroxidation and fibrosis were additive, there was no evidence of a specific synergistic interaction between them. These observations support a model where steatosis exerts an effect on fibrosis through lipid peroxidation, particularly in zone 3 hepatocytes.