Pomegranate Juice Protects Macrophages from Triglyceride Accumulation: Inhibitory Effect on DGAT1 Activity and on Triglyceride BiosynthesisRosenblat M. · Aviram M.
The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences, Rambam Medical Center, Haifa, Israel
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Article / Publication Details
Background/Aims: To analyze the effects of pomegranate juice (PJ) and punicalagin on macrophage triglyceride metabolism. Methods: Triglyceride metabolism was analyzed in PJ- or punicalagin-treated J774A.1 macrophages or in mouse peritoneal macrophages (MPM) harvested from C57BL/6 mice or from paraoxonase 2 (PON2)-deficient mice. Results: PJ (0–50 µM) significantly and dose-dependently decreased the triglyceride content and triglyceride biosynthesis rate in J774A.1 macrophages or in C57BL/6 MPM by about 30%. Similarly, punicalagin, the major PJ polyphenol, inhibited the MPM triglyceride biosynthesis rate by 40%. The triglyceride hydrolytic rate, however, was not significantly affected by PJ or punicalagin. The activity of diacylglycerol acyltransferase 1 (DGAT1; the rate-limiting enzyme in triglyceride biosynthesis) was significantly inhibited, by 54%, in C57BL/6 MPM that were treated with 50 µM PJ or punicalagin, with no significant effect on DGAT1 mRNA or protein expression. Both PJ and punicalagin increased (1.7-fold) MPM PON2 mRNA expression, and PON2 was previously shown to inhibit DGAT1 activity. However, the addition of PJ or punicalagin (50 µM) to microsomes from PON2-deficient MPM still resulted in a significant reduction (50–58%) in DGAT1 activity. Conclusions: We conclude that the inhibitory effect of PJ on triglyceride biosynthesis could be attributed to a direct effect of PJ on DGAT1 activity.
© 2011 S. Karger AG, Basel
- Carmena R, Duriez P, Fruchart JC: Atherogenic lipoprotein particles in atherosclerosis. Circulation 2004;109:III2–III7.
- Cullen P: Evidence that triglycerides are an independent coronary heart disease risk factor. Am J Cardiol 2000;86:943–949.
- Aviram M, Rosenblat M: Paraoxonases 1, 2 and 3, oxidative stress, and macrophage foam cell formation during atherosclerosis development. Free Radic Biol Chem 2004;37:1304–1316.
- Tiwari RL, Singh Y, Barthwal MK: Macrophages: an elusive yet emerging therapeutic target of atherosclerosis. Med Res Rev 2008;28:483–544.
- Lusis AJ: Atherosclerosis. Nature 2000:404:233–241.
- Lundberg B: Chemical composition and physical state of lipid deposits in atherosclerosis. Atherosclerosis 1985;56:93–110.
- Lang PD, Insull W Jr: Lipid droplets in atherosclerotic fatty streaks of human aorta. J Clin Invest 1970;49:1479–1488.
- Mattsson L, Johansson H, Ottosson M, Bondjers G, Wilklund O: Expression of lipoprotein lipase mRNA and secretion in macrophages isolated from human atherosclerotic aorta. J Clin Invest 1993;92:1759–1765.
- Aronis A, Madar Z, Tirosh O: Mechanism underlying oxidative stress-mediated lipotoxicity: exposure of J774.2 macrophages to triacylglycerols facilitates mitochondrial reactive oxygen species production and cellular necrosis. Free Radic Biol Med 2005;38:1221–1230.
- Gil MI, Tomás-Barberán FA, Hess-Pierce B, Holcroft DM, Kader AA: Antioxidant activity of pomegranate juice and its relationship with phenolic composition and processing. J Agric Food Chem 2000;48:4581–4589.
- Tzulker R, Glazer I, Bar-Ilan I, Holland D, Aviram M, Amir R: Antioxidant activity, polyphenol content, and related compounds in different fruit juices and homogenates prepared from 29 different pomegranate accessions. J Agric Food Chem 2007;55:9559–9570.
- Basu A, Penugonda K: Pomegranate juice: a heart-healthy fruit juice. Nutr Rev 2009;67:49–56.
- Aviram M, Dornfeld L, Rosenblat M, Volkova N, Kaplan M, Coleman R, Hayek T, Presser D, Fuhrman B: Pomegranate juice consumption reduces oxidative stress, atherogenic modifications to LDL, and platelet aggregation: studies in humans and in atherosclerotic apolipoprotein E-deficient mice. Am J Clin Nutr 2000;71:1062–1076.
- Aviram M, Rosenblat M, Gaitini D, Nitecki S, Hoffman A, Dornfeld L, Volkova N, Presser D, Attias J, Liker H, Hayek T: Pomegranate juice consumption for 3 years by patients with carotid artery stenosis reduces common carotid intima-media thickness, blood pressure and LDL oxidation. Clin Nutr 2004;23:423–433.
- Davidson MH, Maki KC, Dicklin MR, Feinstein SB, Witchger M, Bell M, McGuire DK, Provost JC, Liker H, Aviram M: Effects of consumption of pomegranate juice on carotid intima-media thickness in men and women at moderate risk for coronary heart disease. Am J Cardiol 2009;104:936–942.
- Rosenblat M, Hayek T, Aviram M: Anti-oxidative effects of pomegranate juice (PJ) consumption by diabetic patients on serum and on macrophages. Atherosclerosis 2006;187:363–371.
- Rock W, Rosenblat M, Miller-Lotan R, Levy AP, Elias M, Aviram M: Consumption of wonderful variety pomegranate juice and extract by diabetic patients increases paraoxonase 1 association with high-density lipoprotein and stimulates its catalytic activities. J Agric Food Chem 2008;56:8704–8713.
- Fuhrman B, Volkova N, Aviram M: Pomegranate juice polyphenols increase recombinant paraoxonase-1 binding to high-density lipoprotein: studies in vitro and in diabetic patients. Nutrition 2010;26:359–366.
- Kaplan M, Hayek T, Raz A, Coleman R, Dornfeld L, Vaya J, Aviram M: Pomegranate juice supplementation to atherosclerotic mice reduces macrophage lipid peroxidation, cellular cholesterol accumulation and development of atherosclerosis. J Nutr 2001;131:2082–2089.
- Aviram M, Volkova N, Coleman R, Dreher M, Reddy MK, Ferreira D, Rosenblat M: Pomegranate phenolics from the peels, arils, and flowers are antiatherogenic: studies in vivo in atherosclerotic apolipoprotein E-deficient (E0) mice and in vitro in cultured macrophages and lipoproteins. J Agric Food Chem 2008;56:1148–1157.
- Fuhrman B, Volkova N, Aviram M: Pomegranate juice inhibits oxidized LDL uptake and cholesterol biosynthesis in macrophages. J Nutr Biochem 2005;16:570–576.
- Draganov DI, Teiber JF, Speelman A, Osawa Y, Sunahara R, La Du BN: Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities. J Lipid Res 2005;46:1239–1247.
Ng CJ, Wadleigh DJ, Gangopadhyay A, Hama S, Grijalva VR, Navab M, Fogelman AM, Reddy ST: Paraoxonase-2 is a ubiquitously expressed protein with antioxidant properties and is capable of preventing cell-mediated oxidative modification of low density lipoprotein. J Biol Chem 2001;76:44444–44449.
- Rosenblat M, Draganov D, Watson CE, Bisgaier CL, La Du BN, Aviram M: Mouse macrophage paraoxonase 2 activity is increased whereas cellular paraoxonase 3 activity is decreased under oxidative stress. Arterioscler Thromb Vasc Biol 2003;23:468–474.
- Ng CJ, Bourquard N, Grijalva V, Hama S, Shih DM, Navab M, Fogelman AM, Lusis AJ, Young S, Reddy ST: Paraoxonase-2 deficiency aggravates atherosclerosis in mice despite lower apolipoprotein-B-containing lipoproteins: anti-atherogenic role for paraoxonase-2. J Biol Chem 2006;281:29491–29500.
- Rosenblat M, Coleman R, Reddy ST, Aviram M: Paraoxonase 2 attenuates macrophage triglyceride accumulation via inhibition of diacylglycerol acyltransferase 1. J Lipid Res 2009;50:870–879.
- Meilin E, Aviram M, Hayek T: Paraoxonase 2 (PON2) decreases high glucose-induced macrophage triglycerides (TG) accumulation, via inhibition of NADPH-oxidase and DGAT1 activity: studies in PON2-deficient mice. Atherosclerosis 2010;208:390–395.
- Shiner M, Fuhrman B, Aviram M: Macrophage paraoxonase 2 (PON2) expression is up-regulated by pomegranate juice phenolic anti-oxidants via PPAR gamma and AP-1 pathway activation. Atherosclerosis 2007;195:313–321.
- Rosenblat M, Volkova N, Aviram M: Pomegranate juice (PJ) consumption antioxidative properties on mouse macrophages, but not PJ beneficial effects on macrophage cholesterol and triglyceride metabolism, are mediated via PJ-induced stimulation of macrophage PON2. Atherosclerosis 2010;212:86–92.
- Lowry OH, Rosebrough NJ, Farr AL, Randall RJ: Protein measurement with the Folin phenol reagent. J Biol Chem 1951;193:265–275.
- Napolitano M, Avella M, Botham KM, Bravo E: Chylomicrons remnant induction of lipid accumulation in J774A.1 macrophages is associated with up-regulation of triacylglycerol synthesis which is not dependent on oxidation of the particles. Biochim Biophys Acta 2003;1631:255–264.
- Vaziri ND, Kim CH, Phan D, Kim S, Liang K: Up-regulation of hepatic acylCoA: diacylglycerol acyltransferase-1 (DGAT1) expression in nephrotic syndrome. Kidney Int 2004;66:262–267.
- Chandak PG, Radovic B, Aflaki E, Kolb D, Buchebner M, Fröhlich E, Magnes C, Sinner F, Haemmerle G, Zechner R, Tabas I, Levak-Frank S, Kratky D: Efficient phagocytosis requires triacylglycerol hydrolysis by adipose triglyceride lipase. J Biol Chem 2010;285:20192–20201.
- Farese RV Jr, Cases S, Smith SJ: Triglyceride synthesis: insights from the cloning of diacylglycerol acyltransferase. Curr Opin Lipidol 2000;11:229–234.
- Cases S, Smith SJ, Zheng YW, Myers HM, Lear SR, Sande E, Nivak S, Collins C, Welch CB, Lusis AJ, Erickson SK, Farese RV Jr: Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis. Proc Natl Acad Sci USA 1998;95:13018–13023.
- Maor I, Kaplan M, Hayek T, Vaya J, Hoffman A, Aviram M: Oxidized monocyte-derived macrophages in aortic atherosclerotic lesion from apolipoprotein E-deficient mice and from human carotid artery contain lipid peroxides and oxysterols. Biochem Biophys Res Commun 2000;269:775–780.
- Moore EH, Napolitano M, Prosperi A, Avella M, Suckling KE, Bravo E, Botham KM: Incorporation of lycopene into chylomicron remnant-like particles enhances their induction of lipid accumulation in macrophages. Biochem Biophys Res Commun2003;312:1216–1219.
- Lehner R, Kusis A: Biosynthesis of triacylglycerol. Prog Lipid Res 1996;35:169–201.
- Coleman RA, Lee DP: Enzymes of triacylglycerol synthesis and their regulation. Prog Lipid Res 2004;43:134–176.
- Yu YH, Zhang Y, Olelkers P, Stephen L, Sturley ST, Rader DJ, Ginsberg HN: Posttranscriptional control of the expression and function of diacylglycerol acyltransferase-1 in mouse adipocytes. J Biol Chem 2002;277:50876–50884.
- Casaschi A, Maiyoh GK, Adeli K, Theriault AG: Increased diacylglycerol acyltransferase activity is associated with triglyceride accumulation in tissues of diet-induced insulin-resistant hyperlipidemic hamsters. Metabolism 2005;54:403–409.
- Casaschi A, Wang Q, Dang K, Richards A, Theriault A: Intestinal apolipoprotein B secretion is inhibited by the flavonoid quercetin: potential role of microsomal triglyceride transfer protein and diacylglycerol acyltransferase. Lipids 2002;37:647–652.
- Casaschi A, Rubio BK, Maiyoh GK, Theriault AG: Inhibitory activity of diacylglycerol acyltransferase (DGAT) and microsomal triglyceride transfer protein (MTP) by the flavonoid, taxifolin, in HepG2 cells: potential role in the regulation of apolipoprotein B secretion. Atherosclerosis 2004;176:247–253.
- Cerdá B, Llorach R, Cerón JJ, Espín JC, Tomás-Barberán FA: Evaluation of the bioavailability and metabolism in the rat of punicalagin, an antioxidant polyphenol from pomegranate juice. Eur J Nutr 2003;42:18–28.
- Aronis A, Madar Z, Tirosh O: Lipotoxic effects of triacylglycerols in J774.2 macrophages. Nutrition 2008;24:167–176.
- Seeram NP, Henning SM, Zhang Y, Suchard M, Li Z, Heber D: Pomegranate juice ellagitannin metabolites are present in human plasma and some persist in urine for up to 48 h. J Nutr 2006;136:2481–2485.
- Kasimsetty SG, Bialonska D, Reddy MK, Ma G, Khan SI, Ferreira D: Colon cancer chemopreventive activities of pomegranate ellagitannins and urolithins. J Agric Food Chem 2010;58:2180–2187.
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