Acetaminophen or paracetamol (APAP) overdose is a common cause of liver injury. Silymarin (SLM) is a hepatoprotective agent widely used for treating liver injury of different origin. In order to evaluate the possible beneficial effects of SLM, Balb/c mice were pretreated with SLM (100 mg/kg b.wt. per os) once daily for three days. Two hours after the last SLM dose, the mice were administered APAP (300 mg/kg b.wt. i.p.) and killed 6 (T6), 12 (T12) and 24 (T24) hours later. SLM-treated mice exhibited a significant reduction in APAP-induced liver injury, assessed according to AST and ALT release and histological examination. SLM treatment significantly reduced superoxide production, as indicated by lower GSSG content, lower HO-1 induction, alleviated nitrosative stress, decreased p-JNK activation and direct measurement of mitochondrial superoxide production in vitro. SLM did not affect the APAP-induced decrease in CYP2E1 activity and expression during the first 12 hrs. Neutrophil infiltration and enhanced expression of inflammatory markers were first detected at T12 in both groups. Inflammation progressed in the APAP group at T24 but became attenuated in SLM-treated animals. Histological examination suggests that necrosis the dominant cell death pathway in APAP intoxication, which is partially preventable by SLM pretreatment. We demonstrate that SLM significantly protects against APAP-induced liver damage through the scavenger activity of SLM and the reduction of superoxide and peroxynitrite content. Neutrophil-induced damage is probably secondary to necrosis development.

1. To compare the effectiveness of different drug forms of silymarin: standardized extract of silymarin (SS), micronized silymarin (MS) and silymarin in the form of phytosome (PS) on dyslipidemia and liver fat accumulation in a model of metabolic syndrome, in non-obese hereditary hypertriglyceridemic rats. The second aim of this study was to slightly uncover the silymarin action on enzymes and proteins involved in cholesterol metabolism and excretion. 2. Silymarin administered to hereditary hypertriglyceridemic rats as dietary supplements (1%) for 4 weeks significantly lowered the plasma levels of triglycerides, total cholesterol and markedly increased HDL cholesterol level. Western blot analyses showed significant increase in the protein expression of CYP7A1 and CYP4A and increase in protein expression of selected ABC transporters. Silymarin in the form of phytosome and micronized silymarin were more effective forms of silymarin. 3. These findings suggest that silymarin may favorably affect the metabolism of cholesterol and triglycerides in rats with metabolic syndrome. Raising HDL levels suggests potentially important anti-atherogenic effect of silymarin. The changes in expression of cytochromes P450 and ABC transporters involved in cholesterol metabolism and excretion could be partially responsible for the hypolipidemic effect of silymarin.

Recent studies suggest that treatment with SGLT-2 inhibitors can reduce hepatic lipid storage and ameliorate non-alcoholic fatty liver disease (NAFLD) development beyond their glycemic benefits. However, the exact mechanism involved is still unclear. We investigated the hepatic metabolic effect of empagliflozin (10 mg/kg/day for eight weeks) on the development of NAFLD and its complications using HHTg rats as a non-obese prediabetic rat model. Empagliflozin treatment reduced neutral triacylglycerols and lipotoxic diacylglycerols in the liver and was accompanied by significant changes in relative mRNA expression of lipogenic enzymes (Scd-1, Fas) and transcription factors (Srebp1, Pparγ). In addition, alterations in the gene expression of cytochrome P450 proteins, particularly Cyp2e1 and Cyp4a, together with increased Nrf2, contributed to the improvement of hepatic lipid metabolism after empagliflozin administration. Decreased circulating levels of fetuin-A improved lipid metabolism and attenuated insulin resistance in the liver and in peripheral tissues. Our results highlight the beneficial effect of empagliflozin on hepatic lipid metabolism and lipid accumulation independent of obesity, with the mechanisms understood to involve decreased lipogenesis, alterations in cytochrome P450 proteins, and decreased fetuin-A. These changes help to alleviate NAFLD symptoms in the early phase of the disease and before the onset of diabetes.

Background Troxerutin (TRX) has a beneficial effect on blood viscosity and platelet aggregation, and is currently used for the treatment of chronic varicosity. Recently, TRX can improve lipid abnormalities, glucose intolerance and oxidative stress in high-fat diet-induced metabolic disorders. In this study, we tested the effect of TRX on metabolic syndrome-associated disorders using a non-obese model of metabolic syndrome–the Hereditary Hypertriglyceridaemic rats (HHTg). Methods Adult male HHTg rats were fed standard diet without or with TRX (150 mg/kg bwt/day for 4 weeks). Results Compared to untreated rats, TRX supplementation in HHTg rats decreased serum glucose (p<0.05) and insulin (p<0.05). Although blood lipids were not affected, TRX decreased hepatic cholesterol concentrations (p<0.01) and reduced gene expression of HMGCR, SREBP2 and SCD1 (p<0.01), involved in cholesterol synthesis and lipid homeostasis. TRX-treated rats exhibited decreased lipoperoxidation and increased activity of antioxidant enzymes SOD and GPx (p<0.05) in the liver. In addition, TRX supplementation increased insulin sensitivity in muscles and epididymal adipose tissue (p<0.05). Elevated serum adiponectin (p<0.05) and decreased muscle triglyceride (p<0.05) helped improve insulin sensitivity. Among the beneficial effects of TRX were changes to cytochrome P450 family enzymes. Hepatic gene expression of CYP4A1, CYP4A3 and CYP5A1 (p<0.01) decreased, while there was a marked elevation in gene expression of CYP1A1 (p<0.01). Conclusion Our results indicate that TRX improves hepatic lipid metabolism and insulin sensitivity in peripheral tissues. As well as ameliorating oxidative stress, TRX can reduce ectopic lipid deposition, affect genes involved in lipid metabolism, and influence the activity of CYP family enzymes.

Silymarin and silybin are widely used for their hepatoprotective properties. Our previous studies confirm positive effect of silymarin on lipoprotein profile and lipid homeostasis. Advanced drug forms may improve the bioavailability of these compounds. In this study, we investigate the effects of silybin in different drug forms (standardized silybin, micronized silybin, and silybin in form of phytosomes) on dyslipidemia and glucose metabolism in hereditary hypertriglyceridemic (HHTg) rats. Male HHTg rats were divided into four groups of seven animals and were fed by experimental diets. Silybin significantly decreased serum level of triglycerides in groups of rats fed by standardized silybin and silybin in form of phytosomes compared to control group. Results show that silybin did not affect the total cholesterol level, but significantly increased the levels of HDL cholesterol in all groups of animals. Silybin in a standardized form had the highest hypotriglyceridemic effect. On the other hand, the micronized form has caused the highest increase of protective HDL and most significantly decreased glucose and insulin levels. Our results suggest that silybin is probably responsible for some positive properties of silymarin. Subsequent dose-dependent studies of silybin action may reveal the intensity of its positive effects on lipid and glucose parameters.