Reduced Plasma Total Cholesterol Levels Research Articles

Implications on growth performance, glucose metabolism, PI3K/AKT pathway, intestinal flora induced by dietary taurine in a high-carbohydrate diet for grass carp (Ctenopharyngodon idella).

An 8-week experiment was performed to investigate the influence on growth performance, plasma biochemistry, glucose metabolism and the insulin pathway of supplementation of dietary taurine to a high-carbohydrate diet for grass carp. In this study, fish were fed diets at one of two carbohydrate levels, 31·49 % (positive control) or 38·61 % (T00). The high-carbohydrate basal diet (T00), without taurine, was supplemented with 0·05 % (T05), 0·10 % (T10), 0·15 % (T15) or 0·20 % (T20) taurine, resulting in six isonitrogenous (30·37 %) and isolipidic (2·37 %) experimental diets. The experimental results showed that optimal taurine level improved significantly weight gain, specific growth rate (SGR), feed utilisation, reduced plasma total cholesterol levels, TAG and promoted insulin-like growth factor level. Glucokinase, pyruvate kinase and phosphoenolpyruvate carboxykinase activities showed a quadratic function model with increasing dietary taurine level, while hexokinase, fatty acid synthetase activities exhibited a positive linear trend. Optimal taurine supplementation in high-carbohydrate diet upregulated insulin receptor (Ir), insulin receptor substrate (Irs1), phosphatidylinositol 3-kinase (pi3k), protein kinase B (akt1), glycogen synthase kinase 3 β (gs3kβ) mRNA level and downregulated insulin-like growth factor (igf-1), insulin-like growth factor 1 receptor (igf-1R) and Fork head transcription factor 1 (foxo1) mRNA level. The above results suggested that optimal taurine level could improve growth performance, hepatic capacity for glycolipid metabolism and insulin sensitivity, thus enhancing the utilisation of carbohydrates in grass carp. Based on SGR, dietary optimal tributyrin taurine supplementation in grass carp was estimated to be 0·08 %.

Xylo-oligosaccharides ameliorate high cholesterol diet induced hypercholesterolemia and modulate sterol excretion and gut microbiota in hamsters

• Xylo-oligosaccharides reduced plasma total cholesterol levels. • Xylo-oligosaccharides increased fecal outputs of neutral and acidic sterols. • Xylo-oligosaccharides increased fecal outputs of short chain fatty acids. • Xylo-oligosaccharides influenced gut microbiota composition. The present study investigated the cholesterol-lowering activity of xylo- oligosaccharides and its associated underlying mechanisms in hamsters. Twenty-four hamsters were randomly divided into three groups and fed one of three diets, namely a low cholesterol diet, a high cholesterol diet (HCD), and an HCD diet with supplementation of 5% xylo -oligosaccharides for 6 weeks. The changes in gut microbiota, fecal neutral and acidic sterols were examined. Results exhibited that xylo- oligosaccharides could significantly reduce plasma total cholesterol, non-high-density lipoprotein cholesterol and total triacylglycerol by 11.24%, 24.89% and 38.72%, respectively (p < 0.05). Such benefits were associated with an increase in fecal outputs of neutral and acidic sterols as well as SCFAs. Furthermore, dietary supplementation with xylo -oligosaccharides could change the composition of gut microbiota. It was therefore concluded that xylo -oligosaccharides supplementation could reduce plasma cholesterol levels, enhance the excretion of neutral and acidic sterols, and promote the production of SCFAs via changing the gut microbiota composition.

Directed remodeling of the mouse gut microbiome inhibits the development of atherosclerosis

The gut microbiome is a malleable microbial community that can remodel in response to a number of factors, including diet, and contribute to the development of several chronic diseases, including atherosclerosis. We devised an in vitro screening protocol of the mouse gut microbiome to discover molecules that can selectively modify bacterial growth. This approach was used to identify cyclic d,l-α-peptides that remodeled the Western diet (WD) gut microbiome toward the low fat diet microbiome state. Daily oral administration of the peptides in WD-fed LDLr−/− mice reduced plasma total cholesterol levels and atherosclerotic plaques. Depletion of the microbiome with antibiotics abrogated these effects. Peptide treatment reprogrammed the microbiome transcriptome, suppressed the production of pro-inflammatory cytokines (including IL-6, TNF-α, and IL-1β), rebalanced levels of short-chain fatty acids and bile acids, improved gut barrier integrity, and increased intestinal T regulatory cells. Directed chemical manipulation provides an additional tool to decipher the chemical biology of the gut microbiome and may advance microbiome-targeted therapeutics.

Deuterium-reinforced polyunsaturated fatty acids protect against atherosclerosis by lowering lipid peroxidation and hypercholesterolemia

Background and aimsOxidative modification of lipoproteins is a crucial step in atherosclerosis development. Isotopic-reinforced polyunsaturated fatty acids (D-PUFAs) are more resistant to reactive oxygen species-initiated chain reaction of lipid peroxidation than regular hydrogenated (H-)PUFAs. We aimed at investigating the effect of D-PUFA treatment on lipid peroxidation, hypercholesterolemia and atherosclerosis development. MethodsTransgenic APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism, were pre-treated with D-PUFAs or control H-PUFAs-containing diet (1.2%, w/w) for 4 weeks. Thereafter, mice were fed a Western-type diet (containing 0.15% cholesterol, w/w) for another 12 weeks, while continuing the D-/H-PUFA treatment. ResultsD-PUFA treatment markedly decreased hepatic and plasma F2-isoprostanes (approx. −80%) and prostaglandin F2α (approx. −40%) as compared to H-PUFA treatment. Moreover, D-PUFAs reduced body weight gain during the study (−54%) by decreasing body fat mass gain (−87%) without altering lean mass. D-PUFAs consistently reduced plasma total cholesterol levels (approx. −25%), as reflected in reduced plasma non-HDL-cholesterol (−28%). Additional analyses of hepatic cholesterol metabolism indicated that D-PUFAs reduced the hepatic cholesterol content (−21%). Sterol markers of intestinal cholesterol absorption and cholesterol breakdown were decreased. Markers of cholesterol synthesis were increased. Finally, D-PUFAs reduced atherosclerotic lesion area formation throughout the aortic root of the heart (−26%). ConclusionsD-PUFAs reduce body weight gain, improve cholesterol handling and reduce atherosclerosis development by reducing lipid peroxidation and plasma cholesterol levels. D-PUFAs, therefore, represent a promising new strategy to broadly reduce rates of lipid peroxidation, and combat hypercholesterolemia and cardiovascular diseases.

BCG lowers plasma cholesterol levels and delays atherosclerotic lesion progression in mice

Background and aimsBacille-Calmette-Guérin (BCG), prepared from attenuated live Mycobacterium bovis, modulates atherosclerosis development as currently explained by immunomodulatory mechanisms. However, whether BCG is pro- or anti-atherogenic remains inconclusive as the effect of BCG on cholesterol metabolism, the main driver of atherosclerosis development, has remained underexposed in previous studies. Therefore, we aimed to elucidate the effect of BCG on cholesterol metabolism in addition to inflammation and atherosclerosis development in APOE*3-Leiden.CETP mice, a well-established model of human-like lipoprotein metabolism. MethodsHyperlipidemic APOE*3-Leiden.CETP mice were fed a Western-type diet containing 0.1% cholesterol and were terminated 6 weeks after a single intravenous injection with BCG (0.75 mg; 5 × 106 CFU). ResultsBCG-treated mice exhibited hepatic mycobacterial infection and hepatomegaly. The enlarged liver (+53%, p = 0.001) coincided with severe immune cell infiltration and a higher cholesterol content (+31%, p = 0.03). Moreover, BCG reduced plasma total cholesterol levels (−34%, p = 0.003), which was confined to reduced nonHDL-cholesterol levels (−36%, p = 0.002). This was due to accelerated plasma clearance of cholesterol from intravenously injected [14C]cholesteryl oleate-labelled VLDL-like particles (t½ −41%, p = 0.002) as a result of elevated hepatic uptake (+25%, p = 0.05) as well as reduced intestinal cholestanol and plant sterol absorption (up to −37%, p = 0.003). Ultimately, BCG decreased foam cell formation of peritoneal macrophages (−18%, p = 0.02) and delayed atherosclerotic lesion progression in the aortic root of the heart. BCG tended to decrease atherosclerotic lesion area (−59%, p = 0.08) and reduced lesion severity. ConclusionsBCG reduces plasma nonHDL-cholesterol levels and delays atherosclerotic lesion formation in hyperlipidemic mice.

Modulation of lipid metabolism with the overexpression of NPC1L1 in mouse liver

Niemann-Pick C1-like 1 protein (NPC1L1), a transporter crucial in intestinal cholesterol absorption, is expressed in human liver but not in murine liver. To elucidate the role of hepatic NPC1L1 on lipid metabolism, we overexpressed NPC1L1 in murine liver utilizing adenovirus-mediated gene transfer. C57BL/6 mice, fed on normal chow with or without ezetimibe, were injected with NPC1L1 adenovirus (L1-mice) or control virus (Null-mice), and lipid analyses were performed five days after the injection. The plasma cholesterol levels increased in L1-mice, and FPLC analyses revealed increased cholesterol contents in large HDL lipoprotein fractions. These fractions, which showed α-mobility on agarose electrophoresis, were rich in apoE and free cholesterol. These lipoprotein changes were partially inhibited by ezetimibe treatment and were not observed in apoE-deficient mice. In addition, plasma and VLDL triglyceride (TG) levels decreased in L1-mice. The expression of microsomal triglyceride transfer protein (MTP) was markedly decreased in L1-mice, accompanied by the reduced protein levels of forkhead box protein O1 (FoxO1). These changes were not observed in mice with increased hepatic de novo cholesterol synthesis. These data demonstrate that cholesterol absorbed through NPC1L1 plays a distinct role in cellular and plasma lipid metabolism, such as the appearance of apoE-rich lipoproteins and the diminished VLDL-TG secretion.

BAS/BSCR54 The hypolipidaemic activity of novel indole-2-carboxamides in Triton WR-1339-induced hyperlipidaemic rats: a comparison with bezafibrate

Using Triton WR-1339-induced hyperlipidaemic rats as an experimental model, we investigated whether compound 1 (N-(3-benzoylphenyl)-1H-indole-2-carboxamide) and 2 (N-(4-benzoylphenyl)-1H-indole-2-carboxamide) novel anti-hyperlipidaemic agents have any effect on plasma triglyceride, total cholesterol (TC)...

Activated polyamine catabolism leads to low cholesterol levels by enhancing bile acid synthesis

Transgenic mice with activated polyamine catabolism due to overexpression of spermidine/spermine N(1)-acetyltransferase (SSAT) have significantly reduced plasma total cholesterol levels. In our study, we show that low cholesterol levels were attributable to enhanced bile acid synthesis in combination with reduced cholesterol absorption. Hepatic cholesterol 7alpha-hydroxylase (CYP7A1), the rate-limiting enzyme catalyzing the conversion of cholesterol to bile acids, plays an important role in the removal of excess cholesterol from the body. We suggest that by reducing activity of Akt activated polyamine catabolism increased the stability and activity of peroxisome proliferator-activated receptor gamma co-activator 1alpha, the critical activator of CYP7A1. This is supported by our finding that the treatment with SSAT activator, N (1) ,N(11)-diethylnorspermine, reduced significantly the amount of phosphorylated (active) Akt in HepG2 cells. In summary, activated-polyamine catabolism is a novel mechanism to regulate bile acid synthesis. Therefore, polyamine catabolism could be a potential therapeutic target to control hepatic CYP7A1 expression.

Antioxidative and hypocholesterolemic activities of water-soluble puerarin glycosides in HepG2 cells and in C57 BL/6J mice

Puerarin is an isoflavone derived from Kudzu roots and has antioxidant and hypocholesterolemic effects; however, its insolubility often limits its biological availability in vivo. Using a novel transglycosylation process, the solubility of puerarin glycosides was increased > 100-fold, but it was not known whether these modified puerarin glycosides maintained biological activities. We found that water-soluble puerarin glycosides fully maintained antioxidant activities compared with puerarin assessed by radical scavenging activity, reducing power assay, superoxide dismutase activity, and non-site-specific hydroxyl radical scavenging activity. Both puerarin and its glycosides also significantly reduced low-density lipoprotein (LDL) oxidation. Mice fed with puerarin glycosides (0.1% w/w) showed significantly reduced plasma total cholesterol levels, thus, we further investigated their hypocholesterolemic mechanisms by assessing several key gene expressions both in vitro and in vivo. Puerarin and its glycosides induced multiple changes in hepatic cholesterol metabolism. The LDL receptor promoter activity was increased dose-dependently in puerarin glycosides-treated HepG2 cells. Accordingly, the expression of LDL receptor mRNA and protein were also significantly increased in HepG2 cells and mouse livers. The transcription and translation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase were down-regulated both in vitro and in vivo. The cholesterol 7α-hydroxylase (CYP7A1) mRNA levels were not affected in vitro but significantly up-regulated in the mouse livers. Collectively, our results show that puerarin and its glycosides are biologically fully active isoflavone and have antioxidant and hypocholesterolemic effects in HepG2 cells and in C57BL/6J mice. In the livers, hypocholesterolemic effects of puerarin glycoside may be achieved by multiple mechanisms including increasing LDL uptake, reducing cholesterol biosynthesis, and possibly enhancing cholesterol degradation.

Combination of dietary phytosterols plus niacin or fenofibrate: effects on lipid profile and atherosclerosis in apo E-KO mice

Patients with mixed dyslipidemias (increased LDL cholesterol and triglyceride as well as low HDL cholesterol levels) benefit from a combination of lipid-modifying drugs such as statins, niacin, fibrates and ezetemibe. However, safety, tolerability and cost are a concern in drug combination therapy. Dietary phytosterols reduce LDL cholesterol, and niacin or fenofibrate primarily reduces triglyceride and increases HDL-cholesterol levels. Thus, we hypothesized that a combination of phytosterols with niacin or fenofibrate will synergistically impact lipoprotein profile and atherogenesis in apo E-KO mice. Phytosterols alone significantly reduced plasma total cholesterol levels (14.1 vs. 16.9 mmol/L, P<.05) and the extent of atherosclerosis (0.42 vs. 0.15 mm 2, P<.05). The addition of fenofibrate to phytosterols increased plasma total cholesterol levels by >50% (14.1 vs. 21.6 mmol/L, P<.05) and decreased HDL-cholesterol concentrations by 50% (0.8 vs. 0.4 mmol/L). These changes were accompanied by slight reductions in the extent of atherosclerosis (0.42 vs. 0.34 mm 2, P>0.05) as compared to controls, suggesting other potential anti-atherogenic effects of fenofibrate. Unlike fenofibrate, niacin caused an increase of 150% ( P<.05) in HDL-cholesterol concentrations and a decrease of 22% ( P<.05) in total cholesterol levels which were associated with significant reductions (65%, P<.05) in atherosclerotic lesion size as compared to controls. Neither the addition of niacin nor of fenofibrate reduced plasma triglyceride levels. In conclusion, the addition of niacin to phytosterols synergistically increases HDL-cholesterol levels, while a combination of phytosterols and fenofibrate results in no synergistic effects in apo E-KO mice. Further studies in other animal models are needed to establish synergetic effects between these lipid-modifying dietary and pharmacological agents.

Tissue Antioxidant Status Differs in Spontaneously Hypertensive Rats Fed Fish Protein or Casein

The present study was designed to determine whether changes in dietary protein source are related to changes in antioxidant status determined by enzyme activities of catalase, superoxide dismutase (SOD), gluthatione peroxidase (GSH-Px) and gluthatione reductase (GSSG-Red) and lipid peroxidation levels in various tissues. Spontaneously hypertensive rats (SHR; 5 wk old) were fed diets containing 20% casein or fish protein for 2 mo. Feeding the fish protein diet lowered blood pressure and reduced plasma total cholesterol levels and SOD activity in all tissues except muscle compared with the casein diet. Feeding fish protein also enhanced GSH level and GSH-Px activity in liver and heart, accompanied by lower lipid peroxidation. In kidney, however, the lower catalase activity in rats fed fish protein was associated with an enhancement in lipid peroxidation. Plasma and VLDL + LDL lipid peroxidation was unaffected by dietary proteins. In conclusion, the fish protein diet did not play a relevant role in plasma antioxidative defense status but increased it in liver and heart compared with the casein diet. Fish protein attenuated the development of hypertension and also decreased plasma total cholesterol concentration. Thus, it enhances protection against cardiovascular diseases.

Cytotoxicity of intratracheally administered coal fly ash: Studies on liver and plasma lipids in rats

The effect of intratracheal administration of coal fly ash has been studied on liver and plasma lipids of rats. Liver total cholesterol, esterified and free cholesterol, triglycerides, free fatty acids, and phospholipid levels were altered at different periods of time after treatment. Fly ash administration significantly reduced plasma total cholesterol levels up to 30 days after treatment and these were reflected both in its free and esterified cholesterol components. Plasma total phospholipids were reduced up to 60 days after fly ash treatment, but phosphatidyl choline content showed reductions up to 30 days after treatment. Plasma lysophosphatidyl choline was reduced 60 days after treatment. Fly ash administration caused peroxidation of liver lipids.