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Published in: Cardiovascular Diabetology 1/2012

Open Access 01-12-2012 | Original investigation

Reduction of n-3 PUFAs, specifically DHA and EPA, and enhancement of peroxisomal beta-oxidation in type 2 diabetic rat heart

Authors: Lianguo Hou, Kaoqi Lian, Min Yao, Yun Shi, Xin Lu, Lijia Fang, Tianbo He, Lingling Jiang

Published in: Cardiovascular Diabetology | Issue 1/2012

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Abstract

Background

There is overwhelming evidence that dietary supplementation with n-3 polyunsaturated fatty acids (PUFAs), mainly EPA (C20:5n-3) and DHA (C22:6n-3), has cardiovascular protective effects on patients with type 2 diabetes mellitus (T2DM) but not on healthy people. Because the T2DM heart increases fatty acid oxidation (FAO) to compensate for the diminished utilization of glucose, we hypothesize that T2DM hearts consume more n-3 PUFAs and, therefore, need more n-3 PUFAs. In the present study, we investigated the changes in cardiac n-3 PUFAs and peroxisomal beta-oxidation, which are responsible for the degradation of PUFAs in a high-fat diet (HFD) and low-dose streptozotocin- (STZ) induced type 2 diabetic rat model.

Methods and results

The capillary gas chromatography results showed that all the n-3 (or omega-3) PUFAs, especially DHA (~50%) and EPA (~100%), were significantly decreased, and the n-6/n-3 ratio (~115%) was significantly increased in the hearts of diabetic rats. The activity of peroxisomal beta-oxidation, which is crucial to very-long-chain and unsaturated FA metabolism (including DHA), was significantly elevated in DM hearts. Additionally, the real-time PCR results showed that the mRNA expression of most peroxisomal beta-oxidation key enzymes were up-regulated in T2DM rat hearts, which might contribute to the reduction of n-3 (or omega-3) PUFAs.

Conclusion

In conclusion, our results indicate that T2DM hearts consume more n-3 PUFAs, especially DHA and EPA, due to exaggerated peroxisomal beta-oxidation.
Appendix
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Literature
1.
go back to reference Fox CS, Coady S, Sorlie PD, D'Agostino RB, Pencina MJ, Vasan RS, Meigs JB, Levy D, Savage PJ: Increasing cardiovascular disease burden due to diabetes mellitus: the Framingham Heart Study. Circulation. 2007, 115 (12): 1544-1550. 10.1161/CIRCULATIONAHA.106.658948.CrossRefPubMed Fox CS, Coady S, Sorlie PD, D'Agostino RB, Pencina MJ, Vasan RS, Meigs JB, Levy D, Savage PJ: Increasing cardiovascular disease burden due to diabetes mellitus: the Framingham Heart Study. Circulation. 2007, 115 (12): 1544-1550. 10.1161/CIRCULATIONAHA.106.658948.CrossRefPubMed
2.
go back to reference Carley AN, Severson DL: Fatty acid metabolism is enhanced in type 2 diabetic hearts. Biochim Biophys Acta. 2005, 1734 (2): 112-126. 10.1016/j.bbalip.2005.03.005.CrossRefPubMed Carley AN, Severson DL: Fatty acid metabolism is enhanced in type 2 diabetic hearts. Biochim Biophys Acta. 2005, 1734 (2): 112-126. 10.1016/j.bbalip.2005.03.005.CrossRefPubMed
3.
go back to reference van de Weijer T, Schrauwen-Hinderling VB, Schrauwen P: Lipotoxicity in type 2 diabetic cardiomyopathy. Cardiovasc Res. 2011, 92 (1): 10-18. 10.1093/cvr/cvr212.CrossRefPubMed van de Weijer T, Schrauwen-Hinderling VB, Schrauwen P: Lipotoxicity in type 2 diabetic cardiomyopathy. Cardiovasc Res. 2011, 92 (1): 10-18. 10.1093/cvr/cvr212.CrossRefPubMed
4.
go back to reference Hu Q, Ishii E, Nakagawa Y: Differential changes in relative levels of arachidonic acid in major phospholipids from rat tissues during the progression of diabetes. J Biochem. 1994, 115 (3): 405-408.PubMed Hu Q, Ishii E, Nakagawa Y: Differential changes in relative levels of arachidonic acid in major phospholipids from rat tissues during the progression of diabetes. J Biochem. 1994, 115 (3): 405-408.PubMed
5.
go back to reference Ovide-Bordeaux S, Grynberg A: Docosahexaenoic acid affects insulin deficiency- and insulin resistance-induced alterations in cardiac mitochondria. Am J Physiol Regul Integr Comp Physiol. 2004, 286 (3): R519-R527. 10.1152/ajpregu.00303.2003.CrossRefPubMed Ovide-Bordeaux S, Grynberg A: Docosahexaenoic acid affects insulin deficiency- and insulin resistance-induced alterations in cardiac mitochondria. Am J Physiol Regul Integr Comp Physiol. 2004, 286 (3): R519-R527. 10.1152/ajpregu.00303.2003.CrossRefPubMed
6.
go back to reference Camoes F, Bonekamp NA, Delille HK, Schrader M: Organelle dynamics and dysfunction: A closer link between peroxisomes and mitochondria. J Inherit Metab Dis. 2009, 32 (2): 163-180. 10.1007/s10545-008-1018-3.CrossRefPubMed Camoes F, Bonekamp NA, Delille HK, Schrader M: Organelle dynamics and dysfunction: A closer link between peroxisomes and mitochondria. J Inherit Metab Dis. 2009, 32 (2): 163-180. 10.1007/s10545-008-1018-3.CrossRefPubMed
7.
go back to reference Vega RB, Huss JM, Kelly DP: The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol Cell Biol. 2000, 20 (5): 1868-1876. 10.1128/MCB.20.5.1868-1876.2000.PubMedCentralCrossRefPubMed Vega RB, Huss JM, Kelly DP: The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol Cell Biol. 2000, 20 (5): 1868-1876. 10.1128/MCB.20.5.1868-1876.2000.PubMedCentralCrossRefPubMed
8.
go back to reference Razny U, Kiec-Wilk B, Wator L, Polus A, Dyduch G, Solnica B, Malecki M, Tomaszewska R, Cooke JP, Dembinska-Kiec A: Increased nitric oxide availability attenuates high fat diet metabolic alterations and gene expression associated with insulin resistance. Cardiovasc Diabetol. 2011, 10: 68-10.1186/1475-2840-10-68.PubMedCentralCrossRefPubMed Razny U, Kiec-Wilk B, Wator L, Polus A, Dyduch G, Solnica B, Malecki M, Tomaszewska R, Cooke JP, Dembinska-Kiec A: Increased nitric oxide availability attenuates high fat diet metabolic alterations and gene expression associated with insulin resistance. Cardiovasc Diabetol. 2011, 10: 68-10.1186/1475-2840-10-68.PubMedCentralCrossRefPubMed
9.
go back to reference Koopmans SJ, Dekker R, Ackermans MT, Sauerwein HP, Serlie MJ, van Beusekom HM, van den Heuvel M, van der Giessen WJ: Dietary saturated fat/cholesterol, but not unsaturated fat or starch, induces C-reactive protein associated early atherosclerosis and ectopic fat deposition in diabetic pigs. Cardiovasc Diabetol. 2011, 10: 64-10.1186/1475-2840-10-64.PubMedCentralCrossRefPubMed Koopmans SJ, Dekker R, Ackermans MT, Sauerwein HP, Serlie MJ, van Beusekom HM, van den Heuvel M, van der Giessen WJ: Dietary saturated fat/cholesterol, but not unsaturated fat or starch, induces C-reactive protein associated early atherosclerosis and ectopic fat deposition in diabetic pigs. Cardiovasc Diabetol. 2011, 10: 64-10.1186/1475-2840-10-64.PubMedCentralCrossRefPubMed
10.
go back to reference Bilbao E, Cajaraville MP, Cancio I: Cloning and expression pattern of peroxisomal beta-oxidation genes palmitoyl-CoA oxidase, multifunctional protein and 3-ketoacyl-CoA thiolase in mussel Mytilus galloprovincialis and thicklip grey mullet Chelon labrosus. Gene. 2009, 443 (1–2): 132-142.CrossRefPubMed Bilbao E, Cajaraville MP, Cancio I: Cloning and expression pattern of peroxisomal beta-oxidation genes palmitoyl-CoA oxidase, multifunctional protein and 3-ketoacyl-CoA thiolase in mussel Mytilus galloprovincialis and thicklip grey mullet Chelon labrosus. Gene. 2009, 443 (1–2): 132-142.CrossRefPubMed
11.
go back to reference Finck BN, Lehman JJ, Leone TC, Welch MJ, Bennett MJ, Kovacs A, Han X, Gross RW, Kozak R, Lopaschuk GD, Kelly DP: The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. J Clin Invest. 2002, 109 (1): 121-130.PubMedCentralCrossRefPubMed Finck BN, Lehman JJ, Leone TC, Welch MJ, Bennett MJ, Kovacs A, Han X, Gross RW, Kozak R, Lopaschuk GD, Kelly DP: The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. J Clin Invest. 2002, 109 (1): 121-130.PubMedCentralCrossRefPubMed
12.
go back to reference Buse JB, Ginsberg HN, Bakris GL, Clark NG, Costa F, Eckel R, Fonseca V, Gerstein HC, Grundy S, Nesto RW, Pignone MP, Plutzky J, Porte D, Redberg R, Stitzel KF, Stone NJ, American Heart Association; American Diabetes Association: Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation. 2007, 115 (1): 114-126.CrossRefPubMed Buse JB, Ginsberg HN, Bakris GL, Clark NG, Costa F, Eckel R, Fonseca V, Gerstein HC, Grundy S, Nesto RW, Pignone MP, Plutzky J, Porte D, Redberg R, Stitzel KF, Stone NJ, American Heart Association; American Diabetes Association: Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation. 2007, 115 (1): 114-126.CrossRefPubMed
13.
go back to reference Chicco AJ, Sparagna GC, McCune SA, Johnson CA, Murphy RC, Bolden DA, Rees ML, Gardner RT, Moore RL: Linoleate-rich high-fat diet decreases mortality in hypertensive heart failure rats compared with lard and low-fat diets. Hypertension. 2008, 52 (3): 549-555. 10.1161/HYPERTENSIONAHA.108.114264.PubMedCentralCrossRefPubMed Chicco AJ, Sparagna GC, McCune SA, Johnson CA, Murphy RC, Bolden DA, Rees ML, Gardner RT, Moore RL: Linoleate-rich high-fat diet decreases mortality in hypertensive heart failure rats compared with lard and low-fat diets. Hypertension. 2008, 52 (3): 549-555. 10.1161/HYPERTENSIONAHA.108.114264.PubMedCentralCrossRefPubMed
14.
go back to reference Baur LA, O'Connor J, Pan DA, Kriketos AD, Storlien LH: The fatty acid composition of skeletal muscle membrane phospholipid: its relationship with the type of feeding and plasma glucose levels in young children. Metabolism. 1998, 47 (1): 106-112. 10.1016/S0026-0495(98)90202-5.CrossRefPubMed Baur LA, O'Connor J, Pan DA, Kriketos AD, Storlien LH: The fatty acid composition of skeletal muscle membrane phospholipid: its relationship with the type of feeding and plasma glucose levels in young children. Metabolism. 1998, 47 (1): 106-112. 10.1016/S0026-0495(98)90202-5.CrossRefPubMed
15.
go back to reference Slee EL, McLennan PL, Owen AJ, Theiss ML: Low dietary fish-oil threshold for myocardial membrane n-3 PUFA enrichment independent of n-6 PUFA intake in rats. J Lipid Res. 2010, 51 (7): 1841-1848. 10.1194/jlr.M004069.PubMedCentralCrossRefPubMed Slee EL, McLennan PL, Owen AJ, Theiss ML: Low dietary fish-oil threshold for myocardial membrane n-3 PUFA enrichment independent of n-6 PUFA intake in rats. J Lipid Res. 2010, 51 (7): 1841-1848. 10.1194/jlr.M004069.PubMedCentralCrossRefPubMed
16.
go back to reference Srinivasan K, Viswanad B, Asrat L, Kaul CL, Ramarao P: Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening. Pharmacol Res. 2005, 52 (4): 313-320. 10.1016/j.phrs.2005.05.004.CrossRefPubMed Srinivasan K, Viswanad B, Asrat L, Kaul CL, Ramarao P: Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening. Pharmacol Res. 2005, 52 (4): 313-320. 10.1016/j.phrs.2005.05.004.CrossRefPubMed
17.
go back to reference Reed MJ, Meszaros K, Entes LJ, Claypool MD, Pinkett JG, Gadbois TM, Reaven GM: A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat. Metabolism. 2000, 49 (11): 1390-1394. 10.1053/meta.2000.17721.CrossRefPubMed Reed MJ, Meszaros K, Entes LJ, Claypool MD, Pinkett JG, Gadbois TM, Reaven GM: A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat. Metabolism. 2000, 49 (11): 1390-1394. 10.1053/meta.2000.17721.CrossRefPubMed
18.
go back to reference Coste TC, Deumer G, Reychler G, Lebecque P, Wallemacq P, Leal T: Influence of pancreatic status and sex on polyunsaturated fatty acid profiles in cystic fibrosis. Clin Chem. 2008, 54 (2): 388-395. 10.1373/clinchem.2007.094623.CrossRefPubMed Coste TC, Deumer G, Reychler G, Lebecque P, Wallemacq P, Leal T: Influence of pancreatic status and sex on polyunsaturated fatty acid profiles in cystic fibrosis. Clin Chem. 2008, 54 (2): 388-395. 10.1373/clinchem.2007.094623.CrossRefPubMed
19.
go back to reference Lepage G, Roy CC: Specific methylation of plasma nonesterified fatty acids in a one-step reaction. J Lipid Res. 1988, 29 (2): 227-235.PubMed Lepage G, Roy CC: Specific methylation of plasma nonesterified fatty acids in a one-step reaction. J Lipid Res. 1988, 29 (2): 227-235.PubMed
20.
go back to reference Osmundsen H, Brodal B, Hovik R: A luminometric assay for peroxisomal beta-oxidation. Effects of fasting and streptozotocin-diabetes on peroxisomal beta-oxidation. Biochem J. 1989, 260 (1): 215-220.PubMedCentralCrossRefPubMed Osmundsen H, Brodal B, Hovik R: A luminometric assay for peroxisomal beta-oxidation. Effects of fasting and streptozotocin-diabetes on peroxisomal beta-oxidation. Biochem J. 1989, 260 (1): 215-220.PubMedCentralCrossRefPubMed
21.
go back to reference Bookout AL, Mangelsdorf DJ: Quantitative real-time PCR protocol for analysis of nuclear receptor signaling pathways. Nucl Recept Signal. 2003, 1: e012.PubMedCentralCrossRefPubMed Bookout AL, Mangelsdorf DJ: Quantitative real-time PCR protocol for analysis of nuclear receptor signaling pathways. Nucl Recept Signal. 2003, 1: e012.PubMedCentralCrossRefPubMed
22.
go back to reference Dirkx E, Schwenk RW, Glatz JF, Luiken JJ, van Eys GJ: High fat diet induced diabetic cardiomyopathy. Prostaglandins Leukot Essent Fatty Acids. 2011, 85 (5): 219-225. 10.1016/j.plefa.2011.04.018.CrossRefPubMed Dirkx E, Schwenk RW, Glatz JF, Luiken JJ, van Eys GJ: High fat diet induced diabetic cardiomyopathy. Prostaglandins Leukot Essent Fatty Acids. 2011, 85 (5): 219-225. 10.1016/j.plefa.2011.04.018.CrossRefPubMed
23.
go back to reference van der Vusse GJ, van Bilsen M, Glatz JF: Cardiac fatty acid uptake and transport in health and disease. Cardiovasc Res. 2000, 45 (2): 279-293. 10.1016/S0008-6363(99)00263-1.CrossRefPubMed van der Vusse GJ, van Bilsen M, Glatz JF: Cardiac fatty acid uptake and transport in health and disease. Cardiovasc Res. 2000, 45 (2): 279-293. 10.1016/S0008-6363(99)00263-1.CrossRefPubMed
24.
go back to reference Pulinilkunnil T, Rodrigues B: Cardiac lipoprotein lipase: metabolic basis for diabetic heart disease. Cardiovasc Res. 2006, 69 (2): 329-340. 10.1016/j.cardiores.2005.09.017.CrossRefPubMed Pulinilkunnil T, Rodrigues B: Cardiac lipoprotein lipase: metabolic basis for diabetic heart disease. Cardiovasc Res. 2006, 69 (2): 329-340. 10.1016/j.cardiores.2005.09.017.CrossRefPubMed
25.
go back to reference An D, Rodrigues B: Role of changes in cardiac metabolism in development of diabetic cardiomyopathy. Am J Physiol Heart Circ Physiol. 2006, 291 (4): H1489-H1506. 10.1152/ajpheart.00278.2006.CrossRefPubMed An D, Rodrigues B: Role of changes in cardiac metabolism in development of diabetic cardiomyopathy. Am J Physiol Heart Circ Physiol. 2006, 291 (4): H1489-H1506. 10.1152/ajpheart.00278.2006.CrossRefPubMed
26.
go back to reference Poirier Y, Antonenkov VD, Glumoff T, Hiltunen JK: Peroxisomal beta-oxidation–a metabolic pathway with multiple functions. Biochim Biophys Acta. 2006, 1763 (12): 1413-1426. 10.1016/j.bbamcr.2006.08.034.CrossRefPubMed Poirier Y, Antonenkov VD, Glumoff T, Hiltunen JK: Peroxisomal beta-oxidation–a metabolic pathway with multiple functions. Biochim Biophys Acta. 2006, 1763 (12): 1413-1426. 10.1016/j.bbamcr.2006.08.034.CrossRefPubMed
27.
go back to reference Ferdinandusse S, Denis S, Dacremont G, Wanders RJ: Studies on the metabolic fate of n-3 polyunsaturated fatty acids. J Lipid Res. 2003, 44 (10): 1992-1997. 10.1194/jlr.M300223-JLR200.CrossRefPubMed Ferdinandusse S, Denis S, Dacremont G, Wanders RJ: Studies on the metabolic fate of n-3 polyunsaturated fatty acids. J Lipid Res. 2003, 44 (10): 1992-1997. 10.1194/jlr.M300223-JLR200.CrossRefPubMed
28.
go back to reference Van Veldhoven PP: Biochemistry and genetics of inherited disorders of peroxisomal fatty acid metabolism. J Lipid Res. 2010, 51 (10): 2863-2895. 10.1194/jlr.R005959.PubMedCentralCrossRefPubMed Van Veldhoven PP: Biochemistry and genetics of inherited disorders of peroxisomal fatty acid metabolism. J Lipid Res. 2010, 51 (10): 2863-2895. 10.1194/jlr.R005959.PubMedCentralCrossRefPubMed
29.
go back to reference Igarashi M, Ma K, Chang L, Bell JM, Rapoport SI: Rat heart cannot synthesize docosahexaenoic acid from circulating alpha-linolenic acid because it lacks elongase-2. J Lipid Res. 2008, 49 (8): 1735-1745. 10.1194/jlr.M800093-JLR200.CrossRefPubMed Igarashi M, Ma K, Chang L, Bell JM, Rapoport SI: Rat heart cannot synthesize docosahexaenoic acid from circulating alpha-linolenic acid because it lacks elongase-2. J Lipid Res. 2008, 49 (8): 1735-1745. 10.1194/jlr.M800093-JLR200.CrossRefPubMed
30.
go back to reference Russo GL: Dietary n-6 and n-3 polyunsaturated fatty acids: from biochemistry to clinical implications in cardiovascular prevention. Biochem Pharmacol. 2009, 77 (6): 937-946. 10.1016/j.bcp.2008.10.020.CrossRefPubMed Russo GL: Dietary n-6 and n-3 polyunsaturated fatty acids: from biochemistry to clinical implications in cardiovascular prevention. Biochem Pharmacol. 2009, 77 (6): 937-946. 10.1016/j.bcp.2008.10.020.CrossRefPubMed
31.
go back to reference Lee JH, O'Keefe JH, Lavie CJ, Marchioli R, Harris WS: Omega-3 fatty acids for cardioprotection. Mayo Clin Proc. 2008, 83 (3): 324-332. 10.4065/83.3.324.CrossRefPubMed Lee JH, O'Keefe JH, Lavie CJ, Marchioli R, Harris WS: Omega-3 fatty acids for cardioprotection. Mayo Clin Proc. 2008, 83 (3): 324-332. 10.4065/83.3.324.CrossRefPubMed
32.
go back to reference Vrablik M, Prusikova M, Snejdrlova M, Zlatohlavek L: Omega-3 fatty acids and cardiovascular disease risk: do we understand the relationship?. Physiol Res. 2009, 58 (Suppl 1): S19-S26.PubMed Vrablik M, Prusikova M, Snejdrlova M, Zlatohlavek L: Omega-3 fatty acids and cardiovascular disease risk: do we understand the relationship?. Physiol Res. 2009, 58 (Suppl 1): S19-S26.PubMed
33.
go back to reference Buchanan J, Mazumder PK, Hu P, Chakrabarti G, Roberts MW, Yun UJ, Cooksey RC, Litwin SE, Abel ED: Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity. Endocrinology. 2005, 146 (12): 5341-5349. 10.1210/en.2005-0938.CrossRefPubMed Buchanan J, Mazumder PK, Hu P, Chakrabarti G, Roberts MW, Yun UJ, Cooksey RC, Litwin SE, Abel ED: Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity. Endocrinology. 2005, 146 (12): 5341-5349. 10.1210/en.2005-0938.CrossRefPubMed
34.
go back to reference Finck BN, Han X, Courtois M, Aimond F, Nerbonne JM, Kovacs A, Gross RW, Kelly DP: A critical role for PPARalpha-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: modulation by dietary fat content. Proc Natl Acad Sci U S A. 2003, 100 (3): 1226-1231. 10.1073/pnas.0336724100.PubMedCentralCrossRefPubMed Finck BN, Han X, Courtois M, Aimond F, Nerbonne JM, Kovacs A, Gross RW, Kelly DP: A critical role for PPARalpha-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: modulation by dietary fat content. Proc Natl Acad Sci U S A. 2003, 100 (3): 1226-1231. 10.1073/pnas.0336724100.PubMedCentralCrossRefPubMed
Metadata
Title
Reduction of n-3 PUFAs, specifically DHA and EPA, and enhancement of peroxisomal beta-oxidation in type 2 diabetic rat heart
Authors
Lianguo Hou
Kaoqi Lian
Min Yao
Yun Shi
Xin Lu
Lijia Fang
Tianbo He
Lingling Jiang
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2012
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/1475-2840-11-126

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