On a new iterative method for solving linear systems and comparison results

AbstractIn Ujević [A new iterative method for solving linear systems, Appl. Math. Comput. 179 (2006) 725–730], the author obtained a new iterative method for solving linear systems, which can be considered as a modification of the Gauss–Seidel method. In this paper, we show that this is a special case from a point of view of projection techniques. And a different approach is established, which is both theoretically and numerically proven to be better than (at least the same as) Ujević's. As the presented numerical examples show, in most cases, the convergence rate is more than one and a half that of Ujević

Znf202 Affects High Density Lipoprotein Cholesterol Levels and Promotes Hepatosteatosis in Hyperlipidemic Mice

Background: The zinc finger protein Znf202 is a transcriptional suppressor of lipid related genes and has been linked to hypoalphalipoproteinemia. A functional role of Znf202 in lipid metabolism in vivo still remains to be established. Methodology and Principal Findings: We generated mouse Znf202 expression vectors, the functionality of which was established in several in vitro systems. Next, effects of adenoviral znf202 overexpression in vivo were determined in normo- as well as hyperlipidemic mouse models. Znf202 overexpression in mouse hepatoma cells mhAT3F2 resulted in downregulation of members of the Apoe/c1/c2 and Apoa1/c3/a4 gene cluster. The repressive activity of Znf202 was firmly confirmed in an apoE reporter assay and Znf202 responsive elements within the ApoE promoter were identified. Adenoviral Znf202 transfer to Ldlr-/- mice resulted in downregulation of apoe, apoc1, apoa1, and apoc3 within 24 h after gene transfer. Interestingly, key genes in bile flux (abcg5/8 and bsep) and in bile acid synthesis (cyp7a1) were also downregulated. At 5 days post-infection, the expression of the aforementioned genes was normalized, but mice had developed severe hepatosteatosis accompanied by hypercholesterolemia and hypoalphalipoproteinemia. A much milder phenotype was observed in wildtype mice after 5 days of hepatic Znf202 overexpression. Interestingly and similar to Ldl-/- mice, HDL-cholesterol levels in wildtype mice were lowered after hepatic Znf202 overexpression. Conclusion/Significance: Znf202 overexpression in vivo reveals an important role of this transcriptional regulator in liver lipid homeostasis, while firmly establishing the proposed key role in the control of HDL levels

Direct intestinal cholesterol secretion contributes significantly to total fecal neutral sterol excretion in mice

Background & Aims: Hepatobiliary secretion is generally believed to be an integral step in the pathway of cholesterol excretion from the body. Here we have investigated the validity of this paradigm in mice. Methods: Cholesterol balance was assessed by measuring intake, excretion, and biliary output in different mouse models. Direct secretion of cholesterol from the luminal side of enterocytes was studied by perfusion of isolated segments of the small intestine in mice. Results: Cholesterol input and output measurements in different mouse models revealed that fecal neutral sterol excretion was higher than the sum of dietary cholesterol intake and biliary cholesterol secretion indicating the existence of an alternative pathway. Here we show that substantial amounts of cholesterol can be secreted directly by enterocytes. Transintestinal cholesterol secretion is a specific process observed throughout the small intestine (proximal > medial > distal). Secretion depended on the presence of a cholesterol acceptor and was strongly stimulated by bile salts and phospholipids. The capacity of the pathway was sufficient to account for the missing cholesterol in the balance studies. The contribution of this pathway to cholesterol excretion in mice is approximately twice that of the biliary pathway. Conclusions: In mice, the intestine plays a significant role in removal of cholesterol from the body

Ezetimibe stimulates faecal neutral sterol excretion depending on abcg8 function in mice

AbstractEzetimibe stimulates faecal neutral sterol (FNS) excretion in mice, which cannot be explained by cholesterol absorption inhibition alone. We investigated whether these effects are mediated via the sterol exporter ATP binding cassette transporter G8 (abcg8). Ezetimibe increased FNS excretion 2.7-fold in WT mice and 1.5-fold in abcg8−/− mice, without affecting biliary cholesterol secretion. Daily FNS excretion exceeded the sum of dietary cholesterol intake and biliary secretion by about 60%. Ezetimibe enhanced this ‘extra’ FNS excretion by 3.5-fold and 1.5-fold in wildtype (WT) and abcg8−/− mice, respectively. Ezetimibe stimulates fecal sterol excretion of non-biliary and non-dietary origin, probably through stimulation of trans-intestinal cholesterol excretion. We show that this effect depends on intact abcg8 function

Trans-intestinal cholesterol efflux is not mediated through high density lipoprotein

Transintestinal cholesterol efflux (TICE) provides an attractive target to increase body cholesterol excretion. At present, the cholesterol donor responsible for direct delivery of plasma cholesterol to the intestine is unknown. In this study, we investigated the role of HDL in TICE. ATP-binding cassette protein A1 deficient (Abca1(-/-)) mice that lack HDL and wild-type (WT) mice were intravenously injected with chylomicron-like emulsion particles that contained radiolabeled cholesterol that is liberated in the liver and partly reenters the circulation. Both groups secreted radiolabeled cholesterol from plasma into intestinal lumen and TICE was unaltered between the two mouse models. To further investigate the role of HDL, we injected HDL with radiolabeled cholesterol in WT mice and Abca1(-/-)xSr-b1(-/-) mice that lack HDL and are also unable to clear HDL via the liver. The intestines of both mice were unable to take up and secrete radiolabeled cholesterol from HDL via TICE. Although a generally accepted major player in the hepatobiliary route-based cholesterol excretion, HDL plays no significant role in TICE in mice.-Vrins, C. L. J., R. Ottenhoff, K. van den Oever, D. R. de Waart, J. K. Kruyt, Y. Zhao, T. J. C. van Berkel, L. M. Havekes, J. M. Aerts, M. van Eck, P. C. N. Rensen, and A. K. Groen. Trans-intestinal cholesterol efflux is not mediated through high density lipoprotein. J. Lipid Res. 2012. 53: 2017-2023

Hepatic Znf202 overexpression causes hepatosteatosis in <i>Ldlr−/−</i> mice only.

<p>Livers were isolated from <i>Ldlr−/−</i> and WT mice 5 days after injection with 2.10⁹pfu of Ad.Znf202 (filled bars) or Ad-mock (empty bars). Cryosections were prepared from Ldlr−/− liver samples and stained with Oil Red-O (A). Hepatic lipids were extracted from homogenized liver samples and cholesterol and TG concentrations were determined (B). Values are expressed as µg lipid per mg tissue protein and are means ± SD (n = 4). * indicates p<0.05.</p

The Znf202 specifically binds to the alleged response elements

<p>−<b>678 and</b> −<b>564 within the</b> −<b>705/−362 region of the mouse apoE promoter.</b> (A) DNA fragments used in this study containing the putative Znf202 binding sequence. The putative consensus sequences are underlined. (B) EMSA with labeled DNA fragments GnT (lanes 1–10), −678 (lanes 11–20), −564 (lanes 21–30), and PHO (lanes 31–35) described above. Reactions contained the indicated amount (0.1–0.6 µg) of whole cell extract made from either control 911 cells, or from 911 cells overexpressing Znf202. Competition experiments using 50-fold excess of unlabeled GnT oligonucleotide (lanes 4,7 and 10), −678 oligonucleotide (lanes 14,17 and 20), or -564 oligonucleotide (lanes 24,27 and 30) confirmed the specificity of Znf202 binding to both GnT elements. Arrowheads indicate the mobility of unbound DNA and Znf202 protein bound DNA.</p

Hepatic Znf202 overexpression reduces HDL-cholesterol in <i>Ldlr−/−</i> and WT mice.

<p>Blood samples were drawn from <i>Ldlr−/−</i> (n = 4; left panels) and WT mice (n = 4; right panels) 5 days after injection with 2.10⁹pfu of Ad.Znf202 (filled bars) or with Ad-mock (open bars) and derived plasma was analyzed for triglyceride and total cholesterol content (A). Lipoprotein profiles were determined from <i>Ldlr−/−</i> (left panels) and WT mice (right panels) 5 days after injection with Ad.Znf202 (triangles) or with Ad-Mock (squares). The elution fractions were tested for triglyceride and total cholesterol content (B). * and ** indicates p<0.05 and p<0.001, respectively.</p

Relative gene expression in livers 5 days after infection with Ad-mock or Ad-Znf202 in Ldlr−/− and wild type mice.

<p>Values are expressed as means ± SD.</p>*<p>Indicates a significant difference (p<0.05) between Ad.Znf202 treated animals and their corresponding Ad.mock treated controls.</p