Nitric oxide mediates the insulin sensitizing effects of β-sitosterol in high fat diet-fed rats.

β-Sitosterol has been shown to have antidiabetic and antioxidant effects in animal models. The objective of the study is to investigate the effects of β-sitosterol on insulin sensitivity, oxidative and nitrosative stress and lipid abnormalities in liver of high fat-fed rat model of insulin resistance (IR) and to assess whether nitric oxide (NO) is involved in its action. Adult male albino Wistar rats of body weight 150-180g were fed either control diet (CON) or high fat diet (HFD). Each dietary group was divided into two and treated or untreated with β-sitosterol (10mg/kgb.w.(-1)day(-1)) for 4weeks. Inhibition of total nitric oxide synthase (NOS) by administration of nitro-l-arginine methyl ester (L-NAME) and inducible NOS (iNOS) by aminoguanidine (AG) in HFD and HFD+ β-sitosterol groups were accomplished to identify the role of NO. After 28days, assays were performed in plasma and liver. HFD-fed rats showed hyperglycemia, hyperinsulinemia, IR, oxidative damage, nitrosative stress, lipid accumulation and elevated serum aminotransferases. Increased expression of iNOS and decreased expression of endothelial NOS (eNOS) were observed in them. Hepatic fat accumulation was further confirmed by histology. The biochemical and histological abnormalities associated with HFD feeding were significantly reduced by β-sitosterol administration. Administration of L-NAME to HFD-fed rats caused decrease in insulin sensitivity and increase in oxidative stress. Co-administration of L-NAME for the last seven days to β-sitosterol-treated HFD rats abolished the glucose lowering effect of β-sitosterol, but the ability to decrease oxidative stress remained unaltered. On the other hand, administration of AG resulted in improved glucose homeostasis and antioxidant levels but decreased oxidative stress and enhanced antioxidant potential in both HFD and HFD+ β-sitosterol treated groups. Thus, β-sitosterol promotes insulin sensitivity in rats fed HFD possibly by improving NO levels. With additional studies, β-sitosterol might be used as a functional drug or as an adjuvant in the management of IR and associated fatty liver disease.

Radika MK ，Viswanathan P ，Anuradha CV 《-》

Suppression of hepatic oxidative events and regulation of eNOS expression in the liver by naringenin in fructose-administered rats.

Previous studies show that naringenin promotes insulin sensitivity in fructose-fed rats. This study investigates whether naringenin prevents oxidative events and apoptotic changes triggered in the rat liver by a high fructose diet. Male Wistar rats of body weight 150-180 g were fed either diet containing starch (60% carbohydrate) or fructose (60% fructose diet). From the 16th day of feeding, rats in each dietary group were divided into two, and treated or not with naringenin (50mg/kg b.w/day). After 60 days, oxidative and nitrosative damage and endothelial nitric oxide synthase (eNOS) expression and hepatocyte apoptosis were determined. To evaluate whether nitric oxide (NO) plays a role in naringenin action, insulin sensitivity indices, fasting plasma glucose and insulin were assessed in response to co-administration of L-nitro-arginine methyl ester (L-NAME), a NOS inhibitor. Fructose feeding caused oxidative damage to proteins and lipids and resulted in reduced antioxidant status, eNOS expression and nitrite level. Increased formation of 4-hydroxy nonenal (4-HNE), 2, 4-dinitrophenol (2, 4-DNP) and 3-nitrotyrosine (3-NT)-modified proteins and the presence of apoptotic nuclei were observed in the liver. Treatment with naringenin attenuated all these parameters to levels not significantly different from control. Treatment with naringenin improved insulin sensitivity. However, L-NAME plus naringenin administration abolished the insulin-sensitizing effects of naringenin in fructose-fed rats. Reduced oxidative events with simultaneous increase in NO bioavailability may be involved in the insulin-sensitizing and cytoprotective effects of naringenin in fructose-fed rats.

Kannappan S ，Palanisamy N ，Anuradha CV 《-》

Chronic blockade of nitric oxide synthesis reduces adiposity and improves insulin resistance in high fat-induced obese mice.

Tsuchiya K ，Sakai H ，Suzuki N ，Iwashima F ，Yoshimoto T ，Shichiri M ，Hirata Y ... -  《ENDOCRINOLOGY》

Ameliorative effect of nicorandil on high fat diet induced non-alcoholic fatty liver disease in rats.

Nonalcoholic fatty liver disease (NAFLD) is an accumulation of excessive amounts of fats in the liver that is not caused by alcohol consumption. It is considered as the most common liver disease in Western societies. The aim of this study is to investigate the possible protective effects of nicorandil and pioglitazone, the benefits of their combination and the possible mechanism underlie these effects in NAFLD. Rats were fed a high-fat diet (HFD) for eight weeks to induce NAFLD. In the next eight weeks, rats were fed the HFD along with pioglitazone (4 mg/kg) or nicorandil in two dose levels (3 or 15 mg/kg), alone or in combination. Chronic HFD administration resulted in significant elevations in serum levels of liver enzymes, total cholesterol, triglycerides, glucose, insulin and HOMA-IR index as compared with the control group. This was coupled with significant increments in liver triglycerides, MDA content and TNF-α as well as a significant reduction in liver GSH content. In comparison with the control group; liver expression of NF-κB was significantly elevated while liver eNOS expression and nitric oxide content were significantly decreased in HFD group. Treatment with pioglitazone or nicorandil either alone or in combination successfully ameliorated the deleterious effects of HFD on the all previous parameters. In conclusion, this investigation indicates a novel role of nicorandil in rats with NAFLD. This effect is mediated through, nitric oxide donor, antioxidant and anti-inflammatory properties, leading to improvement of insulin resistance. It is worth mentioning that the combinations were more effective than the individual drugs.

Elshazly SM 《-》

Chronic administration of aminoguanidine reduces vascular nitric oxide production and attenuates liver damage in bile duct-ligated rats.

Wei CL ，Hon WM ，Lee KH ，Khoo HE ... -  《LIVER INTERNATIONAL》