Silibinin modulates lipid homeostasis and inhibits nuclear factor kappa B activation in experimental nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is associated with increased liver-related mortality. Disturbances in hepatic lipid homeostasis trigger oxidative stress and inflammation (ie, lipotoxicity), leading to the progression of NASH. This study aimed at identifying whether silibinin may influence the molecular events of lipotoxicity in a mouse model of NASH. Eight-week-old db/db mice were fed a methionine-choline deficient (MCD) diet for 4 weeks and treated daily with silibinin (20 mg/kg intraperitoneally) or vehicle. Liver expression and enzyme activity of stearoyl-CoA desaturase-1 and acyl-CoA oxidase, and expression of liver fatty acid-binding protein were assessed. Hepatic levels of reactive oxygen species, thiobarbituric acid-reactive substances (TBARS), 3-nitrotyrosine (3-NT), inducible nitric oxide synthase (iNOS), and nuclear factor kappa B (NFkB) activities were also determined. Silibinin administration decreased serum alanine aminotransferase and improved liver steatosis, hepatocyte ballooning, and lobular inflammation in db/db mice fed an MCD diet. Gene expression and activity of stearoyl-CoA desaturase-1 were reduced in db/db mice fed an MCD diet compared with lean controls and were increased by silibinin; moreover, silibinin treatment induced the expression and activity of acyl-CoA oxidase and the expression of liver fatty acid-binding protein. Vehicle-treated animals displayed increased hepatic levels of reactive oxygen species and TBARS, 3-NT staining, and iNOS expression; silibinin treatment markedly decreased reactive oxygen species and TBARS and restored 3-NT and iNOS to the levels of control mice. db/db mice fed an MCD diet consistently had increased NFkB p65 and p50 binding activity; silibinin administration significantly decreased the activity of both subunits. Silibinin treatment counteracts the progression of liver injury by modulating lipid homeostasis and suppressing oxidative stress-mediated lipotoxicity and NFkB activation in experimental NASH.

Salamone F ，Galvano F ，Cappello F ，Mangiameli A ，Barbagallo I ，Li Volti G ... -  《-》

Silibinin improves hepatic and myocardial injury in mice with nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease is a chronic metabolic disorder with significant impact on cardiovascular and liver mortality. In this study, we examined the effects of silibinin on liver and myocardium injury in an experimental model of nonalcoholic fatty liver disease. A four-week daily dose of silibinin (20 mg/kg i.p.) was administrated to db/db mice fed a methionine-choline deficient diet. Hepatic and myocardial histology, oxidative stress and inflammatory cytokines were evaluated. Silibinin administration decreased HOMA-IR, serum ALT and markedly improved hepatic and myocardial damage. Silibinin reduced isoprostanes, 8-deoxyguanosine and nitrites/nitrates in the liver and in the heart of db/db fed the methionine-choline deficient diet, whereas glutathione levels were restored to lean mice levels in both tissues. Consistently, liver mitochondrial respiratory chain activity was significantly impaired in untreated mice and was completely restored in silibinin-treated animals. TNF-α was increased whereas IL-6 was decreased both in the liver and heart of db/db fed methionine-choline deficient diet. Silibinin reversed heart TNF-α and IL-6 expression to control mice levels. Indeed, liver JNK phosphorylation was reduced to control levels in treated animals. This study demonstrates a combined effectiveness of silibinin on improving liver and myocardial injury in experimental nonalcoholic fatty liver disease.

Salamone F ，Galvano F ，Marino Gammazza A ，Paternostro C ，Tibullo D ，Bucchieri F ，Mangiameli A ，Parola M ，Bugianesi E ，Li Volti G ... -  《-》

Alpha-lipoic acid attenuates methionine choline deficient diet-induced steatohepatitis in C57BL/6 mice.

Non-alcoholic steatohepatitis (NASH) is a liver disease that causes fat accumulation, inflammation and fibrosis. Increased oxidative stress contributes to hepatic inflammation and fibrosis by upregulation of Cytochrome P450 2E1 (CYP2E1), endoplasmic reticulum (ER) stress and mitogen-activated protein kinase (MAPK) activity. This study examined whether alpha-lipoic acid (ALA), a naturally occurring thiol antioxidant, prevents steatohepatitis through the inhibition of several pathways involved in hepatic inflammation and fibrosis. C57BL/6 mice were fed an MCD diet with or without ALA for 4weeks. Liver sections from mice on control or MCD diets with or without ALA were stained with hematoxylin-eosin, oil red O, and anti-4-HNE antibody. The effects of ALA on methionine-choline deficient MCD-diet induced plasma AST and ALT as well as tissue TBARS were measured. The effects of ALA on CYP2E1 expression, ER stress, MAPK levels, and NF-κB activity in MCD diet-fed mice liver were measured by northern and western blot analysis. Dietary supplementation with ALA reduced MCD diet-induced hepatic lipid accumulation, hepatic inflammation, TBARS, 4-HNE, and plasma ALT and AST levels. These effects were associated with a reduced expression of CYP2E1 and reduced ER stress and MAPK and NF-κB activity. Taken together, the results of the present study indicate that ALA attenuates steatohepatitis through inhibition of several pathways, and provide the possibility that ALA can be used to prevent the development and progression of non-alcoholic fatty liver disease in patients who have strong risk factors for NASH.

Min AK ，Kim MK ，Kim HS ，Seo HY ，Lee KU ，Kim JG ，Park KG ，Lee IK ... -  《-》

Pan-caspase inhibitor VX-166 reduces fibrosis in an animal model of nonalcoholic steatohepatitis.

Witek RP ，Stone WC ，Karaca FG ，Syn WK ，Pereira TA ，Agboola KM ，Omenetti A ，Jung Y ，Teaberry V ，Choi SS ，Guy CD ，Pollard J ，Charlton P ，Diehl AM ... -  《-》

Serotonin mediates oxidative stress and mitochondrial toxicity in a murine model of nonalcoholic steatohepatitis.

Nocito A ，Dahm F ，Jochum W ，Jang JH ，Georgiev P ，Bader M ，Renner EL ，Clavien PA ... -  《GASTROENTEROLOGY》