The effects of peroxisome proliferator activated receptors alpha and gamma (PPAR-alpha and PPAR-gamma) and retinoid X receptor (RXR) agonists upon synthesis and accumulation of lipids in murine C57Bl macrophages during inflammation induced by injection of zymosan and Escherichia coli lipopolysaccharide (LPS) have been studied. It is significant that intraperitoneal injection of zymosan (50 mg/kg) or LPS (0.1 mg/kg) in mice led to a dramatic increase of [14C]oleate incorporation into cholesteryl esters and triglycerides and [14C]acetate incorporation into cholesterol and fatty acids in peritoneal macrophages. Lipid synthesis reached its maximum rate 18-24 h after injection and was decreased 5-7 days later to control level after LPS injection or was still heightened after zymosan injection. In macrophages obtained in acute phase of inflammation (24 h), degradation of 125I-labeled native low density lipoprotein (NLDL) was 4-fold increased and degradation of 125I-labeled acetylated LDL (AcLDL) was 2-3-fold decreased. Addition of NLDL (50 microg/ml) or AcLDL (25 microg/ml) into the incubation medium of activated macrophages induced 9-14- and 1.25-fold increase of cholesteryl ester synthesis, respectively, compared with control. Addition of NLDL and AcLDL into the incubation medium completely inhibited cholesterol synthesis in control macrophages but had only slightly effect on cholesterol synthesis in activated macrophages. Injection of RXR, PPAR-alpha, or PPAR-gamma agonists--9-cis-retinoic acid (5 mg/kg), bezafibrate (10 mg/kg), or rosiglitazone (10 mg/kg), respectively--30 min before zymosan or LPS injection led to significant decrease of lipid synthesis. Ten hour preincubation of activated in vivo macrophages with the abovementioned agonists (5 microM) decreased cholesteryl ester synthesis induced by NLDL and AcLDL addition into the cell cultivation medium. The data suggest that RXR, PPAR-alpha, or PPAR-gamma agonists inhibited lipid synthesis and induction of cholesteryl ester synthesis in inflammatory macrophages caused by capture of native or modified LDL.
BackgroundRhaponticum cathamoides (RC) is an endemic wild Siberian herb with marked medicinal properties that are still poorly understood. The aim of this study is to investigate the therapeutic potential of RC extract (ERC) compared to the effects of Glycyrrhiza glabra (EGG) and Punica granatum extracts (EPG) in a rat model with high-fat diet-(HFD)-induced signs of metabolic syndrome; therefore, this study addresses a significant global public health problem.MethodsSix-month-old male Wistar Albino Glaxo rats were subjected to eight weeks of a standard diet (SD), HFD, or HFD in which ERC, EGG, or EPG powders were incorporated at 300 mg/kg/day. The serum lipid profile, corticosterone and cytokine concentrations, glucose tolerance, systolic blood pressure, triacylglycerol accumulation, and PPARα DNA-binding activities in the liver samples were determined.ResultsIn contrast to EGG and EPG, an ERC supplement significantly reduced the weight of epididymal tissue (19.0%, p < 0.01) and basal serum glucose level (19.4%, p < 0.05). ERC improved glucose intolerance as well as dyslipidemia more efficiently than EGG and EPG. EGG but not ERC or EPG supplementation decreased systolic blood pressure by 12.0% (p < 0.05). All of the tested extracts reduced serum IL6 and corticosterone levels induced by HFD. However, the lowering effects of ERC consumption on the serum TNF-α level and its restoring effect on the adrenal corticosterone level significantly exceeded the improvements induced by EGG and EPG. ERC intake also reduced triacylglycerol accumulation and increased the PPARα DNA-binding activity in the liver more significantly than EGG and EPG.ConclusionsERC powder supplementation improved glucose and lipid metabolism more significantly than EGG and EPG in rats fed on HFD, supporting the strategy of R. carthamoides use for safe relief of metabolic syndrome and its related disturbances such as inflammation, stress, and hepatic steatosis.
The role of plasma lipoproteins as carriers in the transport of benzo[a]pyrene was assessed in in vitro and in vivo studies. Addition of [3H]benzo[a]pyrene to rat plasma resulted in binding of the xenobiotic to lipoproteins. Studies of labeled benzo[a]pyrene distribution in rat blood plasma by the method of ultracentrifugation have given the following results: high-density lipoproteins, 40%; low-density lipoproteins, 14%; very-low-density lipoproteins, 23%; other plasma proteins, 23%. Complexes of benzo[a]pyrene-lipoproteins were isolated by gel filtration with Sephadex G-25 and used for intravenous injection in rats. Biodistribution studies have shown different localization of benzo[a]pyrene in rat organs and tissues depending on lipoprotein classes. A high amount or radioactivity was bound by the liver and adrenals when all classes of lipoproteins were used, but especially with high-density lipoproteins. High levels of benzo[a]pyrene were measured in the kidneys. Equilibrium dissociation constants for complexes of benzo[a]pyrene with high-density lipoproteins and low-density lipoproteins were obtained (Kd 4.1 x 10(-5) and 1.5 x 10(-5) M, respectively). Binding and distribution of the protein component of lipoproteins were studied by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. More than 80% of the radioactivity recovered from the gel was localized in the area of apolipoprotein B. After isolation and purification of apolipoprotein B, the equilibrium dissociation constant for complexes of benzo[a]pyrene with apolipoprotein B was obtained, and its value indicated that apolipoprotein B might be the main protein carrier for benzo[a]pyrene.
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