Beneficial effects of voglibose administration on body weight and lipid metabolism via gastrointestinal bile acid modification.

This study was designed with the goal of examining the effects of voglibose administration on body weight and lipid metabolism and underlying mechanism high fat diet-induced obese mice. Male C57BL/6 mice were randomly assigned to one of four groups: a control diet (CTL), high-fat diet (HF), high-fat diet supplemented with voglibose (VO), and high fat diet pair-fed group (PF). After 12 weeks, the following characteristics were investigated: serum lipid and glucose levels, serum polar metabolite profiles, and expression levels of genes involved in lipid and bile acid metabolism. In addition, pyrosequencing was used to analyze the composition of gut microbiota found in feces. Total body weight gain was significantly lower in the VO group than in the CTL, HF, and PF groups. The VO group exhibited improved metabolic profiles including those of blood glucose, triglyceride, and total cholesterol levels. The 12-week voglibose administration decreased the ratio of Firmicutes to Bacteroidetes found in feces. Circulating levels of taurocholic and cholic acid were significantly higher in the VO group than in the HF and CTL groups. Deoxycholic acid levels tended to be higher in the VO group than in the HF group. Voglibose administration downregulated expression levels of CYP8B1 and HNF4α genes and upregulated those of PGC1α, whereas FXRα was not affected. Voglibose administration elicits changes in the composition of the intestinal microbiota and circulating metabolites, which ultimately has systemic effects on body weight and lipid metabolism in mice.

Effects of fisetin supplementation on hepatic lipogenesis and glucose metabolism in Sprague-Dawley rats fed on a high fat diet.

The modulatory effects of daily fisetin supplementation for 8 weeks on genes involved in hepatic lipogenesis and gluconeogenesis and hyperglycemia in rats fed a high fat (HF) diet were evaluated. Elevated levels of triglyceride (TG), along with hepatic TG content and glucose concentrations in a high fat diet group were found to be reduced by fisetin supplementation. The high fat diet significantly increased hepatic mRNA expressions of PPARγ, SREBP1C and SCD-1 genes in comparison to the control diet, which was subsequently reversed by supplementation with fisetin. In addition, fisetin supplementation significantly reduced hepatic mRNA abundance of FAS, ATPCL and G6Pase compared to the control group. Finally, epididymal mRNA abundance of GLUT4 was significantly increased by fisetin supplementation, compared to levels in the control and HF groups. Enhancement of GLUT4 expression by fisetin was further confirmed in differentiated 3T3-L1 adipocytes. Fisetin supplementation decreases cardiovascular risks by ameliorating hepatic steatosis and lowering circulating glucose concentrations.

Hypocholesterolemic effect of daily fisetin supplementation in high fat fed Sprague-Dawley rats.

We aimed to test whether fisetin could modulate cholesterol homeostasis in rats with diet-induced hypercholesterolemia, and further investigated the underlying mechanisms by which fisetin exerts its cholesterol lowering effect. Blood lipid profile, hepatic cholesterol content, as well as gene expressions in cholesterol metabolism were examined. Elevated levels of total cholesterol and LDL-cholesterol, along with hepatic cholesterol content in a high fat group were found to be significantly reduced by fisetin. The high fat diet significantly decreased hepatic mRNA levels of LDLR, SREBP2, HMGCR and PCSK9 in comparison to the control diet, however, fisetin did not further elicit any changes in mRNA levels of the same genes. The high fat diet dramatically increased the transcript levels of CYP7A1, which was subsequently reversed by the fisetin. In HepG2 cells, fisetin was found to increase the levels of a nuclear form of SREBP2 and LDLR. In conclusion, fisetin supplementation displayed hypocholesterolemic effects by modulating the expression of genes associated with cholesterol and bile acid metabolism.

Quercetin up-regulates expressions of peroxisome proliferator-activated receptor γ, liver X receptor α, and ATP binding cassette transporter A1 genes and increases cholesterol efflux in human macrophage cell line.

Cholesterol-laden macrophages trigger accumulation of foam cells and increase the risk of developing atherosclerosis. We hypothesized that quercetin could lower the content of cholesterol in macrophages by regulating the expression of the ATP binding cassette transporter A1 (ABCA1) gene in differentiated human acute monocyte leukemia cell line (THP-1) cells and thereby reducing the chance of forming foam cells. Quercetin, in concentrations up to 30 µM, was not cytotoxic to differentiated THP-1 cells. Quercetin up-regulated both ABCA1 messenger RNA and protein expression in differentiated THP-1 cells, and its maximum effects were demonstrated at 0.3 µM for 4 to 8 hours in incubation. In addition, quercetin increased protein levels of peroxisome proliferator-activated receptor γ (PPARγ) and liver X receptor α (LXRα) within 2 hours of treatment. Because PPARγ and LXRα are important transcriptional factors for ABCA1, quercetin-induced up-regulation of ABCA1 may be mediated by increased expression levels of the PPARγ and LXRα genes. Furthermore, quercetin-enhanced cholesterol efflux from differentiated THP-1 cells to both high-density lipoprotein (HDL) and apolipoprotein A1. Quercetin at the dose of 0.15 µM elevated the cholesterol efflux only for HDL. At the dose of 0.3 µM, quercetin demonstrated effects both on HDL and apolipoprotein A1. Our data demonstrated that quercetin increased the expressions of PPARγ, LXRα, and ABCA1 genes and cholesterol efflux from THP-1 macrophages. Quercetin-induced expression of PPARγ and LXRα might subsequently affect up-regulation of their target gene ABCA1. Taken together, ingestion of quercetin or quercetin-rich foods could be an effective way to improve cholesterol efflux from macrophages, which would contribute to lowering the risk of atherosclerosis.

Plasma phospholipid fatty acid composition in ischemic stroke: importance of docosahexaenoic acid in the risk for intracranial atherosclerotic stenosis.

OBJECTIVE: While data on the relationship between fatty acid (FA) composition and the risk for total stroke have accumulated, the association between FA composition and the risk for intracranial atherosclerotic stenosis (ICAS) has never been studied. We compared plasma phospholipid FA composition between non-stroke control and ischemic stroke in Korean population, to discern the FA that distinguishes ICAS from total ischemic stroke patients. METHODS: Non-stroke controls (n = 215) and stroke patients (no cerebral atherosclerotic stenosis, NCAS: n = 144 and ICAS: n = 104) were finally included in the analysis. Plasma phospholipid FA compositions were analyzed. RESULTS: Age, coexistence of hypertension/diabetes were significantly different among the groups. Phospholipid FA compositions were significantly different between non-stroke control and ischemic stroke patients, and interestingly, between NCAS and ICAS in stroke patients. Pattern analysis showed that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), the ω3-polyunsaturated FAs were important FAs in distinguishing NCAS and ICAS in strokes. Particularly, the risk of ICAS was inversely associated with levels of DHA contents in phospholipids (OR: 0.590, 95% CI: 0.350-0.993, p < 0.05), indicating that the risk may be increased at lower levels of DHA contents. CONCLUSION: DHA and EPA are important FAs for distinguishing NCAS and ICAS in strokes. Additionally, the risk of ICAS was inversely associated with the levels of phospholipid DHA, which indicates that sufficient amounts of DHA in plasma or in diet may reduce the risk of ICAS.

Effects of kimchi supplementation on blood pressure and cardiac hypertrophy with varying sodium content in spontaneously hypertensive rats.

We tested the effects of dietary intake of freeze-dried Korean traditional fermented cabbage (generally known as kimchi) with varying amounts of sodium on blood pressure and cardiac hypertrophy in spontaneously hypertensive rats (SHRs). Wistar-Kyoto rats (WKY), as a control group, received a regular AIN-76 diet, and the SHRs were divided into four groups. The SHR group was fed a regular diet without kimchi supplementation, the SHR-L group was fed the regular diet supplemented with low sodium kimchi containing 1.4% salt by wet weight, which was provided in a freeze-dried form, the SHR-M group was supplemented with medium levels of sodium kimchi containing 2.4% salt, and the SHR-H group was supplemented with high sodium kimchi containing 3.0% salt. Blood pressure was measured over 6 weeks, and cardiac hypertrophy was examined by measuring heart and left ventricle weights and cardiac histology. SHRs showed higher blood pressure compared to that in WKY rats, which was further elevated by consuming high sodium containing kimchi but was not influenced by supplementing with low sodium kimchi. None of the SHR groups showed significant differences in cardiac and left ventricular mass or cardiomyocyte size. Levels of serum biochemical parameters, including blood urea nitrogen, creatinine, glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, sodium, and potassium were not different among the groups. Elevations in serum levels of aldosterone in SHR rats decreased in the low sodium kimchi group. These results suggest that consuming low sodium kimchi may not adversely affect blood pressure and cardiac function even under a hypertensive condition.

Quercetin up-regulates LDL receptor expression in HepG2 cells.

Quercetin, an abundant flavonol found in fruits and vegetable, has been implicated in lowering the risk of cardiovascular disease that is often associated with high plasma levels of low density lipoprotein (LDL) cholesterol. Here we investigated whether quercetin could modulate the expression of LDL receptors (LDLR) in HepG2 cells and the possible underlying mechanisms to exert quercetin's effects. We found that quercetin was able to induce LDLR expression with at least a 75 µ m concentration, which was accompanied by an increase in nuclear sterol regulatory element binding protein 2 (SREBP2). This effect was mediated by activation of c-jun-N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) signalling pathways as implicated by experiments using chemical inhibitors of each pathway. When cells were challenged with protein synthesis inhibitors in quercetin-activated LDLR transcription, LDL mRNA levels were not significantly affected by cycloheximide but puromycin abolished quercetin-induced LDLR transcription. Taken together, we conclude that quercetin can initiate LDLR transcription by enhancing SREBP2 processing, but new protein synthesis might be necessary to exert a maximum effect of quercetin in the up-regulation of the LDLR gene. Our findings demonstrate that quercetin strongly up-regulated LDLR gene expression, which might elicit hypolipidemic effects by increasing the clearance of circulating LDL cholesterol levels from the blood.