lignans and Hypertriglyceridemia

Hyperlipidemia is a risk factor of arteriosclerosis, stroke, and other coronary heart disease, which has been shown to correlate with single nucleotide polymorphisms of genes essential for lipid metabolism, such as lipoprotein lipase (LPL) and apolipoprotein A5 (APOA5). In this study, the effect of magnolol, the main active component extracted from Magnolia officinalis, on LPL activity was investigated. A dose-dependent up-regulation of LPL activity, possibly through increasing LPL mRNA transcription, was observed in mouse 3T3-L1 pre-adipocytes cultured in the presence of magnolol for 6 days. Subsequently, a transgenic knock-in mice carrying APOA5 c.553G>T variant was established and then fed with corn oil with or without magnolol for four days. The baseline plasma triglyceride levels in transgenic knock-in mice were higher than those in wild-type mice, with the highest increase occurred in homozygous transgenic mice (106 mg/dL vs 51 mg/dL, p<0.01). After the induction of hyperglyceridemia along with the administration of magnolol, the plasma triglyceride level in heterozygous transgenic mice was significantly reduced by half. In summary, magnolol could effectively lower the plasma triglyceride levels in APOA5 c.553G>T variant carrier mice and facilitate the triglyceride metabolism in postprandial hypertriglyceridemia.

Topics: 3T3-L1 Cells; Animals; Apolipoprotein A-V; Biphenyl Compounds; Gene Knock-In Techniques; Heterozygote; Humans; Hypertriglyceridemia; Lignans; Lipoprotein Lipase; Magnolia; Mice; Mice, Transgenic; Triglycerides; Up-Regulation

It has been demonstrated that acute oral administration of schisandrin B (Sch B), an active dibenzocyclooctadiene isolated from Schisandrae Fructus (a commonly used traditional Chinese herb), increased serum and hepatic triglyceride (TG) levels and hepatic mass in mice. The present study aimed to investigate the biochemical mechanism underlying the Sch B-induced hypertriglyceridemia, hepatic steatosis and hepatomegaly.. Male ICR mice were given a single oral dose of Sch B (0.25-2 g/kg). Sch B-induced changes in serum levels of biomarkers, such as TG, total cholesterol (TC), apolipoprotein B48 (ApoB 48), very-low-density lipoprotein (VLDL), non-esterified fatty acid (NEFA) and hepatic growth factor (HGF), as well as hepatic lipids and mass, epididymal adipose tissue (EAT) and adipocyte size, and histological changes of the liver and EAT were examined over a period of 12-120 h after Sch B treatment.. Serum and hepatic TG levels were increased by 1.0-4.3 fold and 40-158% at 12-72 h and 12-96 h, respectively, after Sch B administration. Sch B treatment elevated serum ApoB 48 level (up to 12%), a marker of exogenous TG, but not VLDL, as compared with the vehicle treatment. Treatment with Sch B caused a time-/dose-dependent reduction in EAT index (up to 39%) and adipocyte size (up to 67%) and elevation in serum NEFA level (up to 55%). Sch B treatment induced hepatic steatosis in a time-/dose-dependent manner, as indicated by increases in total vacuole area (up to 3.2 fold vs. the vehicle control) and lipid positive staining area (up to 17.5 × 10. Our findings suggest that exogenous sources of TG and the breakdown of fat storage in the body contribute to Sch B-induced hypertriglyceridemia and hepatic steatosis in mice. Hepatomegaly (a probable hepatotoxic action) caused by Sch B may result from the fat accumulation and mitochondrial damage in liver tissue.

Topics: Adipocytes; Adipose Tissue; Animals; Antineoplastic Agents, Phytogenic; Apolipoprotein B-48; Cell Size; Cholesterol; Cholesterol, VLDL; Cyclooctanes; Fatty Acids, Nonesterified; Fatty Liver; Hepatocyte Growth Factor; Hepatomegaly; Hypertriglyceridemia; Lignans; Liver; Male; Mice; Mice, Inbred ICR; Mitochondria; Polycyclic Compounds; Schisandra; Triglycerides

In this study, we aim to identify the potential biomarkers in hTG pathogenesis in schisandrin B-induced hTG mouse model. To investigate whether these identified biomarkers are only specific to schisandrin B-induced hTG mouse model, we also measured these biomarkers in a high fat diet (HFD)-induced hTG mouse model. We employed a LC/MS/MS-based lipidomic approach for the study. Mouse liver and serum metabolites were separated by reversed phase liquid chromatography. Metabolite candidates were identified by matching with marker retention times, isotope distribution patterns, and high-resolution MS/MS fragmentation patterns. Subsequently, target candidates were quantified by quantitative MS. In the schisandrin B-induced hTG mice, we found that the plasma fatty acids, diglyceroids, and phospholipids were significantly increased. Palmitic acid and stearic acid were increased in the plasma; oleic acid, linoleic acid, linolenic acid, arachidonic acid, and docosahexaenoic acid were increased in both the plasma and the liver. Acetyl-CoA, malonyl-CoA, and succinyl-CoA were increased only in the liver. The changes in levels of these identified markers were also observed in HFD-induced hTG mouse model. The consistent results obtained from both hTG models not only suggest novel biomarkers in hTG pathogenesis, but they also provide insight into the underlying mechanism of the schisandrin B-induced hTG.

Topics: Animals; Biomarkers; Calibration; Chromatography, Liquid; Cyclooctanes; Hypertriglyceridemia; Lignans; Lipids; Mice; Polycyclic Compounds; Principal Component Analysis; Reproducibility of Results; Tandem Mass Spectrometry; Triglycerides

Schisandrin B, an active ingredient isolated from the fruit of Schisandra chinensis, increased serum and hepatic triglyceride levels in mice. In the present study, the effective kinetics of schisandrin B on serum/hepatic triglyceride and total cholesterol levels in mice without and with the influence of fenofibrate were investigated. Parameters on hepatic index (the ratio of liver weight to body weight × 100) were also analyzed. Mice were intragastrically treated with schisandrin B at a single dose of 0.2, 0.4, 0.8, or 1.6 g/kg, without or with fenofibrate pretreatment (0.1 g/kg/day for 4 days, p.o.). Twenty-four hours after schisandrin B treatment, serum/hepatic triglyceride and total cholesterol levels were measured. Schisandrin B treatment dose-dependently increased serum and hepatic triglyceride levels as well as hepatic index in mice. In contrast, hepatic total cholesterol levels were decreased in a dose-dependent manner in schisandrin B-treated mice. Data obtained from effective kinetics analysis indicated that the action of schisandrin B on serum triglyceride had a higher specificity than those on hepatic total cholesterol and hepatic index. While fenofibrate pretreatment inhibited the schisandrin B-induced elevation in serum triglyceride levels, it completely abrogated the elevation of hepatic triglyceride levels in schisandrin B-treated mice. The combined treatment with schisandrin B and fenofibrate decreased hepatic total cholesterol level and increased the hepatic index in an additive or semi-additive manner, respectively. In conclusion, the results of effective kinetics analysis indicated that the schisandrin B-induced hypertriglyceridemia was competitively inhibited by fenofibrate. Schisandrin B may offer the prospect of setting up a mouse model of hypertriglyceridemia and fatty liver for screening triglyceride-lowering drug candidates.

Topics: Animals; Cholesterol; Cyclooctanes; Disease Models, Animal; Dose-Response Relationship, Drug; Fenofibrate; Hypertriglyceridemia; Hypolipidemic Agents; Lignans; Liver; Male; Mice; Mice, Inbred ICR; Polycyclic Compounds; Schisandra; Triglycerides

Mice were intragastrically treated with single doses (0.05-0.8 g/kg) of schisandrin B (a dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis). Twenty-four hours after schisandrin B administration, the serum triglyceride level was increased by 10-235% in a dose-dependent manner. However, the serum low density lipoprotein cholesterol level was significantly decreased by 28% at a dose of 0.8 g/kg. When given once daily (0.01-0.2 g/kg) for 4 days, schisandrin B also dose-dependently elevated the serum triglyceride level (17-134%). Kinetics parameters estimated by Scott's plot analysis of schisandrin B-induced changes in serum and hepatic triglyceride levels were determined: serum-E(max) (maximal effect)=6 mmol/L (384% increase, P<0.001); K(D) (affinity)=0.59 mmol/kg; pD(2) (an index of affinity)=6.62; liver-E(max)=21 micromol/g (68% increase, P<0.001); K(D)=0.37 mmol/kg; pD(2)=6.83. The efficacy of schisandrin B in increasing the triglyceride level was 5.6-fold higher in serum than in liver tissue. Fenofibrate (0.2g/kg) treatment, when in combination with schisandrin B (0.2g/kg), for 4 days significantly reduced the schisandrin B-induced increase in serum triglyceride level (by 81%, P<0.001). Hepatic triglyceride level was also decreased (by 100%, P<0.001) by co-treatment with fenofibrate. Our results suggest that schisandrin B treatment can be used to establish a mouse model of acute hypertrigylceridemia.

Topics: Animals; Cyclooctanes; Disease Models, Animal; Fenofibrate; Hypertriglyceridemia; Hypolipidemic Agents; Lignans; Lipids; Liver; Male; Mice; Mice, Inbred ICR; Polycyclic Compounds