Prevention and reversion of nonalcoholic steatohepatitis in OB/OB mice by S-nitroso-N-acetylcysteine treatment.

OBJECTIVE: To evaluate the role oral administration of S-nitroso-N-acetylcysteine (SNAC), a NO donor drug, in the prevention and reversion of NASH in two different animal models. METHODS: NASH was induced in male ob/ob mice by methionine-choline deficient (MCD) and high-fat (H) diets. Two animal groups received or not SNAC orally for four weeks since the beginning of the treatment. Two other groups were submitted to MCD and H diets for 60 days receiving SNAC only from the 31(st) to the 60(th) day. RESULTS: SNAC administration inhibited the development of NASH in all groups, leading to a marked decrease in macro and microvacuolar steatosis and in hepatic lipid peroxidation in the MCD group. SNAC treatment reversed the development of NASH in animals treated for 60 days with MCD or H diets, which received SNAC only from the 31(st) to the 60(th) day. CONCLUSIONS: Oral administration of SNAC markedly inhibited and reversed NASH induced by MCD and H diets in ob/ob mice.

Oral administration of S-nitroso-N-acetylcysteine prevents the onset of non alcoholic fatty liver disease in rats.

AIM: To evaluate the potential of S-nitroso-N-acetylcysteine (SNAC) in inhibition of lipid peroxidation and the effect of oral SNAC administration in the prevention of nonalcoholic fatty liver disease (NAFLD) in an animal model. METHODS: NAFLD was induced in Wistar male rats by choline-deficient diet for 4 wk. SNAC-treated animals (n=6) (1.4 mg/kg per day of SNAC, orally) were compared to 2 control groups: one (n=6) received PBS solution and the other (n=6) received NAC solution (7 mg/kg per day). Histological variables were semiquantitated with respect to macro and microvacuolar fat changes, its zonal distribution, foci of necrosis, portal and perivenular fibrosis, and inflammatory infiltrate with zonal distribution. LOOHs from samples of liver homogenates were quantified by HPLC. Nitrate levels in plasma of portal vein were assessed by chemiluminescence. Aqueous low-density lipoprotein (LDL) suspensions (200 microg protein/mL) were incubated with CuCl(2) (300 micromol/L) in the absence and presence of SNAC (300 micromol/L) for 15 h at 37 degree Celsius. Extent of LDL oxidation was assessed by fluorimetry. Linoleic acid (LA) (18.8 micromol/L) oxidation was induced by soybean lipoxygenase (SLO) (0.056 micromol/L) at 37 degree Celsius in the presence and absence of N-acetylcysteine (NAC) and SNAC (56 and 560 micromol/L) and monitored at 234 nm. RESULTS: Animals in the control group developed moderate macro and microvesicular fatty changes in periportal area. SNAC-treated animals displayed only discrete histological alterations with absence of fatty changes and did not develop liver steatosis. The absence of NAFLD in the SNAC-treated group was positively correlated with a decrease in the concentration of LOOH in liver homogenate, compared to the control group (0.7+/-0.2 nmol/mg vs 3.2+/-0.4 nmol/mg protein, respectively, P<0.05), while serum levels of aminotransferases were unaltered. The ability of SNAC in preventing lipid peroxidation was confirmed in in vitro experiments using LA and LDL as model substrates. CONCLUSION: Oral administration of SNAC prevents the onset of NAFLD in Wistar rats fed with choline-deficient diet. This effect is correlated with the ability of SNAC to block the propagation of lipid peroxidation in vitro and in vitro.