Atherosclerosis in aged mice over-expressing the reverse cholesterol transport genes

We determined whether over-expression of one of the three genes involved in reverse cholesterol transport, apolipoprotein (apo) AI, lecithin-cholesterol acyl transferase (LCAT) and cholesteryl ester transfer protein (CETP), or of their combinations influenced the development of diet-induced atherosclerosis. Eight genotypic groups of mice were studied (AI, LCAT, CETP, LCAT/AI, CETP/AI, LCAT/CETP, LCAT/AI/CETP, and non-transgenic) after four months on an atherogenic diet. The extent of atherosclerosis was assessed by morphometric analysis of lipid-stained areas in the aortic roots. The relative influence (R²) of genotype, sex, total cholesterol, and its main sub-fraction levels on atherosclerotic lesion size was determined by multiple linear regression analysis. Whereas apo AI (R² = 0.22, P < 0.001) and CETP (R² = 0.13, P < 0.01) expression reduced lesion size, the LCAT (R² = 0.16, P < 0.005) and LCAT/AI (R² = 0.13, P < 0.003) genotypes had the opposite effect. Logistic regression analysis revealed that the risk of developing atherosclerotic lesions greater than the 50th percentile was 4.3-fold lower for the apo AI transgenic mice than for non-transgenic mice, and was 3.0-fold lower for male than for female mice. These results show that apo AI overexpression decreased the risk of developing large atherosclerotic lesions but was not sufficient to reduce the atherogenic effect of LCAT when both transgenes were co-expressed. On the other hand, CETP expression was sufficient to eliminate the deleterious effect of LCAT and LCAT/AI overexpression. Therefore, increasing each step of the reverse cholesterol transport per se does not necessarily imply protection against atherosclerosis while CETP expression can change specific athero genic scenarios.39139

Reversible flow of cholesteryl ester between high-density lipoproteins and triacylglycerol-rich particles is modulated by the fatty acid composition and concentration of triacylglycerols

We determined the influence of fasting (FAST) and feeding (FED) on cholesteryl ester (CE) flow between high-density lipoproteins (HDL) and plasma apoB-lipoprotein and triacylglycerol (TG)-rich emulsions (EM) prepared with TG-fatty acids (FAs). TG-FAs of varying chain lengths and degrees of unsaturation were tested in the presence of a plasma fraction at d > 1.21 g/mL as the source of CE transfer protein. The transfer of CE from HDL to FED was greater than to FAST TG-rich acceptor lipoproteins, 18% and 14%, respectively. However, percent CE transfer from HDL to apoB-containing lipoproteins was similar for FED and FAST HDL. The CE transfer from HDL to EM depended on the EM TG-FA chain length. Furthermore, the chain length of the monounsaturated TG-containing EM showed a significant positive correlation of the CE transfer from HDL to EM (r = 0.81, P < 0.0001) and a negative correlation from EM to HDL (r = -041, P = 0.0088). Regarding the degree of EM TG-FAs unsaturation, among EMs containing C18, the CE transfer was lower from HDL to C18:2 compared to C18:1 and C18:3, 17.7%, 20.7%, and 20%, respectively. However, the CE transfer from EMs to HDL was higher to C18:2 than to C18:1 and C18:3, 83.7%, 51.2%, and 46.3%, respectively. Thus, the EM FA composition was found to be the rate-limiting factor regulating the transfer of CE from HDL. Consequently, the net transfer of CE between HDL and TG-rich particles depends on the specific arrangement of the TG acyl chains in the lipoprotein particle core431211351142FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP95/7662-

Opposite lipemic response of Wistar rats and C57BL/6 mice to dietary glucose or fructose supplementation

The metabolic effects of carbohydrate supplementation in mice have not been extensively studied. In rats, glucose- and fructose-rich diets induce hypertriacylglycerolemia. In the present study, we compared the metabolic responses to two monosaccharide supplementations in two murine models. Adult male Wistar rats (N = 80) and C57BL/6 mice (N = 60), after 3 weeks on a standardized diet, were submitted to dietary supplementation by gavage with glucose (G) or fructose (F) solutions (500 g/L), 8 g/kg body weight for 21 days. Glycemia was significantly higher in rats after fructose treatment (F: 7.9 vs 9.3 mM) and in mice (G: 6.5 vs 10 and F: 6.6 vs 8.9 mM) after both carbohydrate treatments. Triacylglycerolemia increased significantly 1.5 times in rats after G or F supplementation. Total cholesterol did not change with G treatment in rats, but did decrease after F supplementation (1.5 vs 1.4 mM, P < 0.05). Both supplementations in rats induced insulin resistance, as suggested by the higher Homeostasis Model Assessment Index. In contrast, mice showed significant decreases in triacylglycerol (G: 1.8 vs 1.4 and F: 1.9 vs 1.4 mM, P < 0.01) and total cholesterol levels (G and F: 2.7 vs 2.5 mM, P < 0.05) after both monosaccharide supplementations. Wistar rats and C57BL/6 mice, although belonging to the same family (Muridae), presented opposite responses to glucose and fructose supplementation regarding serum triacylglycerol, free fatty acids, and insulin levels after monosaccharide treatment. Thus, while Wistar rats developed features of plurimetabolic syndrome, C57BL/6 mice presented changes in serum biochemical profile considered to be healthier for the cardiovascular system.32333

Plasma Lipases And Lipid Transfer Proteins Increase Phospholipid But Not Free Cholesterol Transfer From Lipid Emulsion To High Density Lipoproteins

Background: Plasma lipases and lipid transfer proteins are involved in the generation and speciation of high density lipoproteins. In this study we have examined the influence of plasma lipases and lipid transfer protein activities on the transfer of free cholesterol (FC) and phospholipids (PL) from lipid emulsion to human, rat and mouse lipoproteins. The effect of the lipases was verified by incubation of labeled (3H-FC, 14C-PL) triglyceride rich emulsion with human plasma (control, post-heparin and post-heparin plus lipase inhibitor), rat plasma (control and post-heparin) and by the injection of the labeled lipid emulsion into control and heparinized functionally hepatectomized rats. Results: In vitro, the lipase enriched plasma stimulated significantly the transfer of 14C-PL from emulsion to high density lipoprotein (p&lt;0.001) but did not modify the transfer of 3H-FC. In hepatectomized rats, heparin stimulation of intravascular lipolysis increased the plasma removal of 14C-PL and the amount of 14C-PL found in the low density lipoprotein density fraction but not in the high density lipoprotein density fraction. The in vitro and in vivo experiments showed that free cholesterol and phospholipids were transferred from lipid emulsion to plasma lipoproteins independently from each other. The incubation of human plasma, control and control plus monoclonal antibody anti-cholesteryl ester transfer protein (CETP), with 14C-PL emulsion showed that CETP increases 14C-PL transfer to human HDL, since its partial inhibition by the anti-CETP antibody reduced significantly the 14C-PL transfer (p&lt;0.05). However, comparing the nontransgenic (no CETP activity) with the CETP transgenic mouse plasma, no effect of CETP on the 14C-PL distribution in mice lipoproteins was observed. Conclusions: It is concluded that: 1-intravascular lipases stimulate phospholipid transfer protein mediated phospholipid transfer, but not free cholesterol, from triglyceride rich particles to human high density lipoproteins and rat low density lipoproteins and high density lipoproteins; 2-free cholesterol and phospholipids are transferred from triglyceride rich particles to plasma lipoproteins by distinct mechanisms, and 3 - CETP also contributes to phospholipid transfer activity in human plasma but not in transgenic mice plasma, a species which has high levels of the specific phospholipid transfer protein activity.219Backer, G., Bacquer, D., Konitzer, M., Epidemiological aspects of high density lipoprotein cholesterol (1998) Atherosclerosis, 137, pp. S1-S6Stein, O., Stein, Y., Atheroprotective mechanisms of HDL (1999) Atherosclerosis, 144, pp. 285-301Tall, A.R., Plasma lipid transfer proteins (1995) Annu Rev Biochem, 64, pp. 235-257Hesler, B., Tall, A.R., Swenson, T.L., Weech, P.K., Marcel, Y.L., Milne, R.W., Monoclonal antibody to the Mr 74000 cholesterol ester transfer protein neutralize all of the cholesterol ester and triglyceride transfer activities in human plasma (1988) J Biol Chem, 263, pp. 5020-5023Swenson, T.L., Brocia, R.W., Tall, A.R., Plasma cholesteryl ester transfer protein has binding sites for neutral lipids and phospholipids (1988) J Biol Chem, 263, pp. 5150-5157Lagrost, L., Athias, A., Gambert, P., Lallemant, C., Comparative study of phospholipid transfer activities mediated by cholesteryl ester transfer protein and phospholipid transfer protein (1994) J Lipid Res, 35, pp. 825-835Tato, F., Vega, G.L., Grundy, S.M., Determinants of plasma HDL-cholesterol in hypertriglyceridemic patients (1997) Arterioscler Thromb Vasc Biol, 17, pp. 56-63Tall, A.R., Forester, L.R., Bongiovanni, G.L., Facilitation of phosphatidylcholine transfer into HDL lipoproteins by an apolipoprotein in the density 1.20-1.26 g/ml fraction of plasma (1983) J Lipid Res, 24, pp. 277-289Albers, J.J., Tollefson, J.H., Chen, C.H., Steinmetz, A., Isolation and characterization of human plasma lipid transfer proteins (1984) Arteriosclerosis, 4, pp. 49-58Guyard-Dangremont, V., Desrumaux, C., Gambert, P., Lallemant, C., Lagrost, L., Phospholipid and cholesteryl ester transfer activities in plasma from 14 vertebrate species. Relation to atherogenesis susceptibility (1998) Comp Biochem Physiol Biochem Mol Biol, 120, pp. 517-525Tall, A.R., Krumholz, S., Olivecrona, T., Deckelbaum, R.J., Plasma phospholipid transfer protein enhances transfer and exchange of phospholipids between VLDL and HDL lipoproteins during lipolysis (1985) J Lipid Res, 26, pp. 842-851Nishida, H.I., Nishida, T., Phospholipid transfer protein mediates transfer of not only phosphatidylcholine but also cholesterol from phosphatidylcholine-cholesterol vesicles to high density lipoproteins (1997) J Biol Chem, 272, pp. 6959-6964Lagrost, L., Desrumaux, C., Masson, D., Deckert, V., Gambert, P., Structure and function of the plasma phospholipid transfer protein (1998) Curr Opin Lipidol, 9, pp. 203-209Albers, J.J., Tu, A.Y., Paigen, B., Chen, H., Cheung, M.C., Marcovina, S.M., Transgenic mice expressing human phospholipid transfer protein have increased HDL/non-HDL cholesterol ratio (1996) Int J Clin Lab Res, 26, pp. 262-267Foger, B., Santamarina-Fojo, S., Shamburek, R.D., Parrot, C.L., Talley, G.D., Brewer Jr., H.B., Plasma phospholipid transfer protein. Adenovirus-mediated overexpression in mice leads to decreased plasma high density lipoprotein (HDL) and enhanced hepatic uptake of phospholipids and cholesteryl esters from HDL (1997) J Biol Chem, 272, pp. 27393-27400Redgrave, T.G., Small, D.M., Quantitation of the transfer of surface phospholipid of chylomicrons to the HDL lipoprotein fraction during the catabolism of chylomicrons in the rat (1979) J Clin Invest, 64, pp. 162-171Tall, A.R., Green, P.H., Glickman, R.M., Riley, J.W., Metabolic fate of chylomicron phospholipids and apoproteins in the rat (1979) J Clin Invest, 64, pp. 977-989Tall, A.R., Blum, C.B., Forester, G.P., Nelson, C.A., Changes in the distribution and composition of plasma HDL liproteins after ingestion of fat (1982) J Biol Chem, 257, pp. 198-207Groot, H., Scheek, L.M., Effects of fat ingestion on HDL profiles in human sera (1984) J Lipid Res, 25, pp. 684-692Brunzell, J.D., Familial lipoprotein lipase deficiency and other causes of the chylomicronemia syndrome (1995) Metabolic & Molecular Bases of Inherited Disease, pp. 1913-1932. , Scriver, CR, Beaudet, AL, Sly, WS, ed, McGraw-Hill Inc, New York, 7th edBijvoet, S., Gagne, S.E., Moorjani, S., Gagne, C., Henderson, H.E., Fruchart, J.C., Dallongeville, J., Hayden, M.R., Alterations in plasma lipoproteins and apolipoproteins before the age of 40 in heterozygotes for lipoprotein lipase deficiency (1996) J Lipid Res, 37, pp. 640-650Kuusi, T., Ehnholm, C., Viikari, J., Harkonen, R., Vartiainen, E., Puska, P., Taskinen, M.-R., Postheparin plasma lipoprotein and hepatic lipase are determinants of hypo- and hyperalphalipoproteinemia (1989) J Lipid Res, 30, pp. 1117-1126Liu, S., Jirik, F.R., LeBoeuf, R.C., Henderson, H., Castellani, L.W., Lusis, A.J., Ma, Y., Kirk, E., Alteration of lipid profiles in plasma of transgenic mice expressing human lipoprotein lipase (1994) J Biol Chem, 269, pp. 11417-11424Weinstock, P.H., Bisgaier, C.L., Aalto-Setala, K., Radner, H., Ramakrishnan, R., Levak-Frank, S., Essenburg, A.D., Breslow, J.L., Severe hypertriglyceridemia, reduced high density lipoprotein, and neonatal death in lipoprotein lipase knockout mice. Mild hypertriglyceridemia with impaired very low density lipoprotein clearance in heterozygotes (1995) J Clin Invest, 96, pp. 2555-2568Applebaum-Bowden, D., Kobayashi, J., Kashyap, V.S., Brown, D.R., Berard, A., Meyn, S., Parrott, C., Santamarina-Fojo, S., Hepatic lipase gene therapy in hepatic lipase-deficient mice. Adenovirus-mediated replacement of a lipolytic enzyme to the vascular endothelium (1996) J Clin Invest, 97, pp. 799-805Gillett, M.P., Vieira, E.M., Dimenstein, R., The phospholipase activities present in preheparin mouse plasma are inhibited by antiserum to hepatic lipase (1993) Int J Biochem, 25, pp. 449-453Ha, Y.C., Barter, P.J., Differences in plasma cholesteryl ester transfer activity in sixteen vertebrate species (1982) Comp Biochem Physiol B, 71, pp. 265-269Clee, S.M., Zhang, H., Bissada, N., Miao, L., Ehrenborg, E., Benlian, P., Shen, G.X., Hayden, M.R., Relationship between lipoprotein lipase and HDL lipoprotein cholesterol in mice: Modulation by cholesteryl ester transfer protein and dietary status (1997) J Lipid Res, 38, pp. 2079-2089Oliveira, H.C.F., Hirata, M.H., Redgrave, T.G., Maranhão, R.C., Competition between chylomicrons and their remnants for plasma removal: A study with artificial emulsion models of chylomicrons (1988) Biochim Biophys Acta, 958, pp. 211-217Nakandakare, E.R., Lottenberg, S.A., Oliveira, H.C.F., Bertolami, M.C., Vasconcelos, K.S., Sperotto, G., Quintão, E.C., Simultaneous measurements of chylomicron lipolysis and remnant removal using a doubly labeled artificial lipid emulsion: Studies in normolipidemic and hyperlipidemic subjects (1994) J Lipid Res, 35, pp. 143-152Jiao, S., Cole, T.G., Kitchens, R.T., Pfleger, B., Schonfeld, G., Genetic heterogeneity of lipoproteins in inbred strains of mice: Analysis by gel-permeation chromatography (1990) Metabolism, 39, pp. 155-160Ehnholm, C., Kuusi, T., Preparation, characterization and measurement of hepatic lipase (1986) Methods Enzymol, 129, pp. 716-738Oliveira, H.C.F., Quintão, E.C., 'In vitro' cholesteryl ester bidirectional flow between high-density lipoproteins and triglyceride-rich emulsions: Effects of particle concentration and composition, cholesteryl ester transfer activity and oleic acid (1996) J Biochem Biophys Methods, 32, pp. 45-57Huff, M.W., Miller, D.B., Wolf, B.M., Connelly, P.W., Sawyez, C.G., Uptake of hypertriglyceridemic VLDL and their remnants by HepG2 cells: The role of lipoprotein lipase, hepatic triglyceride lipase, and cell surface proteoglycans (1997) J Lipid Res, 38, pp. 1318-1333Marques-Vidal, P., Jauhiainen, M., Metso, J., Ehnholm, C., Transformation of HDL2 particles by hepatic lipase and phospholipid transfer protein (1997) Atherosclerosis, 133, pp. 87-96Murdoch, S.J., Breckenridge, W.C., Effect of lipid transfer proteins on lipoprotein lipase induced transformation of VLDL and HDL (1996) Biochim Biophys Acta, 1303, pp. 222-232Murdoch, S.J., Breckenridge, W.C., Influence of lipoprotein lipase and hepatic lipase on the transformation of VLDL and HDL during lipolysis of VLDL (1995) Atherosclerosis, 118, pp. 193-212Patsch, J.R., Gotto Jr., A.M., Olivercrona, T., Eisenberg, S., Formation of HDL2-like particles during lipolysis of VLDL in vitro (1978) Proc Natl Acad Sci USA, 75, pp. 4519-4523Gillett, M.P., Costa, E.M., Owen, J.S., The phospholipase activities present in preheparin mouse plasma are inhibited by antiserum to hepatic lipase (1980) Biochim Biophys Acta, 617, pp. 237-244Peterson, J., Bengtsson-Olivecrona, G., Olivecrona, T., Mouse preheparin plasma contains high levels of hepatic lipase with low affinity for heparin (1986) Biochim Biophys Acta, 87, pp. 865-870O'Meara, N.M., Cabana, V.G., Lukens, J.R., Loharikar, B., Forte, T.M., Polonsky, K.S., Getz, G.S., Heparin-induced lipolysis in hypertriglyceridemic subjects results in the formation of atypical HDL particle (1994) J Lipid Res, 35, pp. 2178-219

Liver Proteomic Response To Hypertriglyceridemia In Human-apolipoprotein C-iii Transgenic Mice At Cellular And Mitochondrial Compartment Levels

Background: Hypertriglyceridemia (HTG) is defined as a triglyceride (TG) plasma level exceeding 150 mg/dl and is tightly associated with atherosclerosis, metabolic syndrome, obesity, diabetes and acute pancreatitis. The present study was undertaken to investigate the mitochondrial, sub-mitochondrial and cellular proteomic impact of hypertriglyceridemia in the hepatocytes of hypertriglyceridemic transgenic mice (overexpressing the human apolipoproteinC-III). Methods. Quantitative proteomics (2D-DIGE) analysis was carried out on both "low-expressor" (LE) and "high- expressor" (HE) mice, respectively exhibiting moderate and severe HTG, to characterize the effect of the TG plasma level on the proteomic response. Results: The mitoproteome analysis has revealed a large-scale phenomenon in transgenic mice, i.e. a general down-regulation of matricial proteins and up-regulation of inner membrane proteins. These data also demonstrate that the magnitude of proteomic changes strongly depends on the TG plasma level. Our different analyses indicate that, in HE mice, the capacity of several metabolic pathways is altered to promote the availability of acetyl-CoA, glycerol-3-phosphate, ATP and NADPH for TG de novo biosynthesis. The up-regulation of several cytosolic ROS detoxifying enzymes has also been observed, suggesting that the cytoplasm of HTG mice is subjected to oxidative stress. Moreover, our results suggest that iron over-accumulation takes place in the cytosol of HE mice hepatocytes and may contribute to enhance oxidative stress and to promote cellular proliferation. Conclusions: These results indicate that the metabolic response to HTG in human apolipoprotein C-III overexpressing mice may support a high TG production rate and that the cytosol of hepatocytes is subjected to an important oxidative stress, probably as a result of FFA over-accumulation, iron overload and enhanced activity of some ROS-producing catabolic enzymes. © 2014 Ehx et al.; licensee BioMed Central Ltd.131Grundy, S.M., Brewer Jr., H.B., Cleeman, J.I., Smith Jr., S.C., Lenfant, C., Definition of Metabolic Syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on Scientific Issues Related to Definition (2004) Circulation, 109 (3), pp. 433-438. , DOI 10.1161/01.CIR.0000111245.75752.C6Reid, A.E., Nonalcoholic steatohepatitis (2001) Gastroenterology, 121 (3), pp. 710-723Toskes, P.P., Hyperlipidemic pancreatitis (1990) Gastroenterol Clin North Am, 19, pp. 783-791Ginsberg, H.N., Ngoc-Anh, L., Goldberg, I.J., Apolipoprotein B metabolism in subjects with deficiency of apolipoproteins CIII and AI. 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Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo e on the particles (1992) J Clin Invest, 90, pp. 1889-1900Reaven, G.M., Mondon, C.E., Chen, Y.-D.I., Breslow, J.L., Hypertriglyceridemic mice transgenic for the human apolipoprotein C-III gene are neither insulin resistant nor hyperinsulinemic (1994) Journal of Lipid Research, 35 (5), pp. 820-824Alberici, L.C., Oliveira, H.C.F., Patricio, P.R., Kowaltowski, A.J., Vercesi, A.E., Hyperlipidemic Mice Present Enhanced Catabolism and Higher Mitochondrial ATP-Sensitive K+ Channel Activity (2006) Gastroenterology, 131 (4), pp. 1228-1234. , DOI 10.1053/j.gastro.2006.07.021, PII S0016508506016647Salerno, A.G., Silva, T.R., Amaral, M.E.C., Alberici, L.C., Bonfleur, M.L., Patricio, P.R., Francesconi, E.P.M.S., Oliveira, H.C.F., Overexpression of apolipoprotein CIII increases and CETP reverses diet-induced obesity in transgenic mice (2007) International Journal of Obesity, 31 (10), 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Decomposition and nutrient release of leguminous plants in coffee agroforestry systems.

Leguminous plants used as green manure are an important nutrient source for coffee plantations, especially for soils with low nutrient levels. Field experiments were conducted in the Zona da Mata of Minas Gerais State, Brazil to evaluate the decomposition and nutrient release rates of four leguminous species used as green manures (Arachis pintoi, Calopogonium mucunoides, Stizolobium aterrimum and Stylosanthes guianensis) in a coffee agroforestry system under two different climate conditions. The initial N contents in plant residues varied from 25.7 to 37.0 g kg-1 and P from 2.4 to 3.0 g kg-1. The lignin/N, lignin/polyphenol and(lignin+polyphenol)/N ratios were low in all residues studied. Mass loss rates were highest in the first 15 days, when 25 % of the residues were decomposed. From 15 to 30 days, the decomposition rate decreased on both farms. On the farm in Pedra Dourada (PD), the decomposition constant k increased in the order C. mucunoides < S. aterrimum < S. guianensis < A. pintoi. On the farm in Araponga (ARA), there was no difference in the decomposition rate among leguminous plants. The N release rates varied from 0.0036 to 0.0096 d-1. Around 32 % of the total N content in the plant material was released in the first 15 days. In ARA, the N concentration in the S. aterrimum residues was always significantly higher than in the other residues. At the end of 360 days, the N released was 78 % in ARA and 89 % in PD of the initial content. Phosphorus was the most rapidly released nutrient (k values from 0.0165 to 0.0394 d-1). Residue decomposition and nutrient release did not correlate with initial residue chemistry and biochemistry, but differences in climatic conditions between the two study sites modified the decomposition rate constants

Green manure in coffee systems in the region of Zona da Mata, Minas Gerais: characteristics and kinetics of carbon and nitrogen mineralization.

The use of green manure may contribute to reduce soil erosion and increase the soil organic matter content and N availability in coffee plantations in the Zona da Mata, State of Minas Gerais, in Southeastern Brazil. The potential of four legumes (A. pintoi, C. mucunoides, S. aterrimum and S. guianensis)to produce above-ground biomass, accumulate nutrients and mineralize N was studied in two coffee plantations of subsistence farmers under different climate conditions. The biomass production of C. mucunoides was influenced by the shade of the coffee plantation.C. mucunoides tended to mineralize more N than the other legumes due to the low polyphenol content and polyphenol/N ratio. In the first year, the crop establishment of A. pintoi in the area took longer than of the other legumes, resulting in lower biomass production and N2 fixation. In the long term, cellulose was the main factor controlling N mineralization. The biochemical characteristics, nutrient accumulation and biomass production of the legumes were greatly influenced by the altitude and position of the area relative to the sun