© 1997 American Heart Association, Inc.
Articles |
Regulation of Lipoprotein Metabolism by Thiazolidinediones Occurs through a Distinct but Complementary Mechanism Relative to Fibrates
From the U.325 INSERM, Département d'Athérosclérose, Institut Pasteur, 1 Rue Calmette, Lille, France; Department of Biochemistry and Molecular Biology, University of Barcelona, Spain (J.P.-O.); Ligand Pharmaceuticals Inc., San Diego, Calif (M.R.B., J.R.P.).
Correspondence to Dr. Bart Staels, INSERM U.325, Institut Pasteur, 1, rue du Prof. Calmette, 59019 Lille Cédex, France.
Abstract Thiazolidinediones are antidiabetic agents, which
not only improve glucose metabolism but also reduce blood
triglyceride concentrations. These compounds are synthetic
ligands for PPAR
, a transcription factor belonging to the nuclear
receptor subfamily of PPARs, which are important transcriptional
regulators of lipid and lipoprotein metabolism. The goal of
this study was to evaluate the influence of a potent thiazolidinedione,
BRL49653, on serum lipoproteins and to determine whether its
lipid-lowering effects are mediated by changes in the expression of key
genes implicated in lipoprotein metabolism. Treatment of
normal rats for 7 days with BRL49653 decreased serum
triglycerides in a dose-dependent fashion without affecting
serum total and HDL cholesterol and apolipoprotein (apo)
A-I and apo A-II concentrations. The decrease in
triglyceride concentrations after BRL49653 was mainly due
to a reduction of the amount of VLDL particles of unchanged lipid and
apo composition. BRL49653 treatment did not change
triglyceride production in vivo as analyzed
by injection of Triton WR-1339, indicating a primary action on
triglyceride catabolism. Analysis of the influence
of BRL49653 on the expression of LPL and apo C-III, two key players in
triglyceride catabolism, showed a dose-dependent increase
in mRNA levels and activity of LPL in epididymal adipose tissue,
whereas liver apo C-III mRNA levels remained constant. Furthermore,
addition of BRL49653 to primary cultures of differentiated adipocytes
increased LPL mRNA levels, indicating a direct action of the drug on
the adipocyte. Simultaneous administration of BRL49653 and
fenofibrate, a hypolipidemic drug that acts primarily on liver through
activation of PPAR
both decreased liver apo C-III and increased
adipose tissue LPL mRNA levels, resulting in a more pronounced lowering
of serum triglycerides than each drug alone. In conclusion,
both fibrates and thiazolidinediones exert a
hypotriglyceridemic effect. While fibrates act
primarily on the liver by decreasing apo C-III production,
BRL49653 acts primarily on adipose tissue by increasing lipolysis
through the induction of LPL expression. Drugs combining both PPAR
and activation potential should therefore display a more efficient
hypotriglyceridemic activity than either compound
alone and may provide a rationale for improved therapy for elevated
triglycerides.
Key Words: gene regulation • atherosclerosis • PPAR • triglycerides • hypolipidemic drugs
This article has been cited by other articles:
 |
|
 |
|
  M. Laplante, W. T. Festuccia, G. Soucy, P.-G. Blanchard, A. Renaud, J. P. Berger, G. Olivecrona, and Y. Deshaies Tissue-specific postprandial clearance is the major determinant of PPAR{gamma}-induced triglyceride lowering in the rat Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2009; 296(1): R57 - R66. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Biscetti and R. Pola Endothelial Progenitor Cells and Angiogenesis Join the PPARty Circ. Res., July 3, 2008; 103(1): 7 - 9. [Full Text] [PDF]
|
|
|
|
 |
|
 F. Biscetti, E. Gaetani, A. Flex, T. Aprahamian, T. Hopkins, G. Straface, G. Pecorini, E. Stigliano, R. C. Smith, F. Angelini, et al. Selective Activation of Peroxisome Proliferator-Activated Receptor (PPAR){alpha} and PPAR{gamma} Induces Neoangiogenesis Through a Vascular Endothelial Growth Factor-Dependent Mechanism Diabetes, May 1, 2008; 57(5): 1394 - 1404. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Laplante, W. T. Festuccia, G. Soucy, Y. Gelinas, J. Lalonde, and Y. Deshaies Involvement of adipose tissues in the early hypolipidemic action of PPAR{gamma} agonism in the rat Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2007; 292(4): R1408 - R1417. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. A. Hanniman, G. Lambert, Y. Inoue, F. J. Gonzalez, and C. J. Sinal Apolipoprotein A-IV is regulated by nutritional and metabolic stress: involvement of glucocorticoids, HNF-4{alpha}, and PGC-1{alpha} J. Lipid Res., November 1, 2006; 47(11): 2503 - 2514. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Cardona, S. Morcillo, M. Gonzalo-Marin, L. Garrido-Sanchez, M. Macias-Gonzalez, and F. J. Tinahones Pro12Ala Sequence Variant of the PPARG Gene Is Associated with Postprandial Hypertriglyceridemia in Non-E3/E3 Patients with the Metabolic Syndrome Clin. Chem., October 1, 2006; 52(10): 1920 - 1925. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. D. Mooradian, M. J. Haas, and N. C. W. Wong The Effect of Select Nutrients on Serum High-Density Lipoprotein Cholesterol and Apolipoprotein A-I Levels Endocr. Rev., February 1, 2006; 27(1): 2 - 16. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Reifel-Miller, K. Otto, E. Hawkins, R. Barr, W. R. Bensch, C. Bull, S. Dana, K. Klausing, J.-A. Martin, R. Rafaeloff-Phail, et al. A Peroxisome Proliferator-Activated Receptor {alpha}/{gamma} Dual Agonist with a Unique in Vitro Profile and Potent Glucose and Lipid Effects in Rodent Models of Type 2 Diabetes and Dyslipidemia Mol. Endocrinol., June 1, 2005; 19(6): 1593 - 1605. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Wagner, P. J. Larson, S. Weiss, J. L. Miller, T. W. Doebber, M. S. Wu, D. E. Moller, and K. M. Gottesdiener Individual and Combined Effects of Peroxisome Proliferator-Activated Receptor and {gamma} Agonists, Fenofibrate and Rosiglitazone, on Biomarkers of Lipid and Glucose Metabolism in Healthy Nondiabetic Volunteers J. Clin. Pharmacol., May 1, 2005; 45(5): 504 - 513. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Knouff and J. Auwerx Peroxisome Proliferator-Activated Receptor-{gamma} Calls for Activation in Moderation: Lessons from Genetics and Pharmacology Endocr. Rev., December 1, 2004; 25(6): 899 - 918. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Li and C. K. Glass PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis J. Lipid Res., December 1, 2004; 45(12): 2161 - 2173. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Berthiaume, H. Sell, J. Lalonde, Y. Gelinas, A. Tchernof, D. Richard, and Y. Deshaies Actions of PPAR{gamma} agonism on adipose tissue remodeling, insulin sensitivity, and lipemia in absence of glucocorticoids Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2004; 287(5): R1116 - R1123. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. D. Hegarty, S. M. Furler, N. D. Oakes, E. W. Kraegen, and G. J. Cooney Peroxisome Proliferator-Activated Receptor (PPAR) Activation Induces Tissue-Specific Effects on Fatty Acid Uptake and Metabolism in Vivo--A Study Using the Novel PPAR{alpha}/{gamma} Agonist Tesaglitazar Endocrinology, July 1, 2004; 145(7): 3158 - 3164. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. A. Brinton, M. N. Nanjee, and P. N. Hopkins Triglyceride-rich lipoprotein remnant levels and metabolism: Time to adopt these orphan risk factors? J. Am. Coll. Cardiol., June 16, 2004; 43(12): 2233 - 2235. [Full Text] [PDF]
|
|
|
|
 |
|
 T. Ueno, J. Tremblay, J. Kunes, J. Zicha, Z. Dobesova, Z. Pausova, A. Y. Deng, Y.-L. Sun, H. J. Jacob, and P. Hamet Rat model of familial combined hyperlipidemia as a result of comparative mapping Physiol Genomics, March 12, 2004; 17(1): 38 - 47. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D. Mooradian, M. J. Haas, and N. C.W. Wong Transcriptional Control of Apolipoprotein A-I Gene Expression in Diabetes Diabetes, March 1, 2004; 53(3): 513 - 520. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Yajima, H. Hirose, H. Fujita, Y. Seto, H. Fujita, K. Ukeda, K. Miyashita, T. Kawai, Y. Yamamoto, T. Ogawa, et al. Combination therapy with PPARgamma and PPARalpha agonists increases glucose-stimulated insulin secretion in db/db mice Am J Physiol Endocrinol Metab, May 1, 2003; 284(5): E966 - E971. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Gauthier, G. Vassiliou, F. Benoist, and R. McPherson Adipocyte Low Density Lipoprotein Receptor-related Protein Gene Expression and Function Is Regulated by Peroxisome Proliferator-activated Receptor gamma J. Biol. Chem., March 28, 2003; 278(14): 11945 - 11953. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Laplante, H. Sell, K. L. MacNaul, D. Richard, J. P. Berger, and Y. Deshaies PPAR-{gamma} Activation Mediates Adipose Depot-Specific Effects on Gene Expression and Lipoprotein Lipase Activity: Mechanisms for Modulation of Postprandial Lipemia and Differential Adipose Accretion Diabetes, February 1, 2003; 52(2): 291 - 299. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. D. Mooradian, M. J. Haas, J. Chehade, and N. C.W. Wong Apolipoprotein A-I Expression in Rats Is Not Altered by Troglitazone Experimental Biology and Medicine, December 1, 2002; 227(11): 1001 - 1005. [Abstract] [Full Text]
|
|
|
|
|
|
A. Carpentier, C. Taghibiglou, N. Leung, L. Szeto, S. C. Van Iderstine, K. D. Uffelman, R. Buckingham, K. Adeli, and G. F. Lewis Ameliorated Hepatic Insulin Resistance Is Associated with Normalization of Microsomal Triglyceride Transfer Protein Expression and Reduction in Very Low Density Lipoprotein Assembly and Secretion in the Fructose-fed Hamster J. Biol. Chem., August 2, 2002; 277(32): 28795 - 28802. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R Mead and D. P Ramji The pivotal role of lipoprotein lipase in atherosclerosis Cardiovasc Res, August 1, 2002; 55(2): 261 - 269. [Full Text] [PDF]
|
|
|
|
|
|
L. Madsen, M. Guerre-Millo, E. N. Flindt, K. Berge, K. J. Tronstad, E. Bergene, E. Sebokova, A. C. Rustan, J. Jensen, S. Mandrup, et al. Tetradecylthioacetic acid prevents high fat diet induced adiposity and insulin resistance J. Lipid Res., May 1, 2002; 43(5): 742 - 750. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Barbier, I. P. Torra, Y. Duguay, C. Blanquart, J.-C. Fruchart, C. Glineur, and B. Staels Pleiotropic Actions of Peroxisome Proliferator-Activated Receptors in Lipid Metabolism and Atherosclerosis Arterioscler. Thromb. Vasc. Biol., May 1, 2002; 22(5): 717 - 726. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Soria, C. Bocos, and E. Herrera Opposite metabolic response to fenofibrate treatment in pregnant and virgin rats J. Lipid Res., January 1, 2002; 43(1): 74 - 81. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Carroll and D. L. Severson Peroxisome proliferator-activated receptor-{alpha} ligands inhibit cardiac lipoprotein lipase activity Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H888 - H894. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. D. Oakes, P. G. Thalén, S. M. Jacinto, and B. Ljung Thiazolidinediones Increase Plasma-Adipose Tissue FFA Exchange Capacity and Enhance Insulin-Mediated Control of Systemic FFA Availability Diabetes, May 1, 2001; 50(5): 1158 - 1165. [Abstract] [Full Text]
|
|
|
|
|
|
Z. Chen, S. Ishibashi, S. Perrey, J.-i. Osuga, T. Gotoda, T. Kitamine, Y. Tamura, H. Okazaki, N. Yahagi, Y. Iizuka, et al. Troglitazone Inhibits Atherosclerosis in Apolipoprotein E-Knockout Mice : Pleiotropic Effects on CD36 Expression and HDL Arterioscler. Thromb. Vasc. Biol., March 1, 2001; 21(3): 372 - 377. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Wolfrum, C. M. Borrmann, T. Börchers, and F. Spener Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors alpha - and gamma -mediated gene expression via liver fatty acid binding protein: A signaling path to the nucleus PNAS, February 15, 2001; (2001) 51619898. [Abstract] [Full Text]
|
|
|
|
 |
|
 P. J. A. Davies, S. A. Berry, G. L. Shipley, R. H. Eckel, N. Hennuyer, D. L. Crombie, K. M. Ogilvie, J. Peinado-Onsurbe, C. Fievet, M. D. Leibowitz, et al. Metabolic Effects of Rexinoids: Tissue-Specific Regulation of Lipoprotein Lipase Activity Mol. Pharmacol., February 1, 2001; 59(2): 170 - 176. [Abstract] [Full Text]
|
|
|
|
 |
|
 U. SMITH, S. GOGG, A. JOHANSSON, T. OLAUSSON, V. ROTTER, and B. SVALSTEDT Thiazolidinediones (PPAR{gamma} agonists) but not PPAR{alpha} agonists increase IRS-2 gene expression in 3T3-L1 and human adipocytes FASEB J, January 1, 2001; 15(1): 215 - 220. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Cox, D. A. Ryan, F. J. Hollis, A.-M. Harris, A. K. Miller, M. Vousden, and H. Cowley Absorption, Disposition, and Metabolism of Rosiglitazone, a Potent Thiazolidinedione Insulin Sensitizer, in Humans Drug Metab. Dispos., July 1, 2000; 28(7): 772 - 780. [Abstract] [Full Text]
|
|
|
|
|
|
E. Raspé, L. Madsen, A-M. Lefebvre, I. Leitersdorf, L. Gelman, J. Peinado-Onsurbe, J. Dallongeville, J-C. Fruchart, R. Berge, and B. Staels Modulation of rat liver apolipoprotein gene expression and serum lipid levels by tetradecylthioacetic acid (TTA) via PPAR{alpha} activation J. Lipid Res., November 1, 1999; 40(11): 2099 - 2110. [Abstract] [Full Text]
|
|
|
|
|
|
S. Sreenan, S. Keck, T. Fuller, B. Cockburn, and C. F. Burant Effects of troglitazone on substrate storage and utilization in insulin-resistant rats Am J Physiol Endocrinol Metab, June 1, 1999; 276(6): E1119 - E1129. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Andersson, Z. Majd, A.-M. Lefebvre, G. Martin, A. V. Sechkin, V. Kosykh, J.-C. Fruchart, J. Najib, and B. Staels Developmental and Pharmacological Regulation of Apolipoprotein C-II Gene Expression : Comparison With Apo C-I and Apo C-III Gene Regulation Arterioscler. Thromb. Vasc. Biol., January 1, 1999; 19(1): 115 - 121. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ranganathan and P. A. Kern Thiazolidinediones Inhibit Lipoprotein Lipase Activity in Adipocytes J. Biol. Chem., October 2, 1998; 273(40): 26117 - 26122. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Nishizawa, K. Yamagata, I. Shimomura, M. Takahashi, H. Kuriyama, K. Kishida, K. Hotta, H. Nagaretani, N. Maeda, M. Matsuda, et al. Small Heterodimer Partner, an Orphan Nuclear Receptor, Augments Peroxisome Proliferator-activated Receptor gamma Transactivation J. Biol. Chem., January 4, 2002; 277(2): 1586 - 1592. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Wolfrum, C. M. Borrmann, T. Borchers, and F. Spener Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors alpha - and gamma -mediated gene expression via liver fatty acid binding protein: A signaling path to the nucleus PNAS, February 27, 2001; 98(5): 2323 - 2328. [Abstract] [Full Text] [PDF]
|
|