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Endocrinology Vol. 144, No. 6 2201-2207
Copyright © 2003 by The Endocrine Society

Minireview: Lipid Metabolism, Metabolic Diseases, and Peroxisome Proliferator-Activated Receptors

Chih-Hao Lee, Peter Olson and Ronald M. Evans

Howard Hughes Medical Institute, Gene Expression Laboratory (C.-H.L., P.O., R.M.E.), The Salk Institute for Biological Studies, La Jolla, California 92037; and Department of Biology (P.O.), University of California, San Diego, La Jolla, California 92037

Address all correspondence and requests for reprints to: Ronald M. Evans, Ph.D., Howard Hughes Medical Institute, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037. E-mail: evans{at}salk.edu.

Lipid and carbohydrate homeostasis in higher organisms is under the control of an integrated system that has the capacity to rapidly respond to metabolic changes. The peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors that have been implicated to play an important role in obesity-related metabolic diseases such as hyperlipidemia, insulin resistance, and coronary artery disease. The three PPAR subtypes, {alpha}, {gamma}, and {delta}, have distinct expression patterns and evolved to sense components of different lipoproteins and regulate lipid homeostasis based on the need of a specific tissue. Recent advances in identifying selective ligands in conjunction with microarray analyses and gene targeting studies have helped delineate the subtype-specific functions and the therapeutic potential of these receptors. PPAR{alpha} potentiates fatty acid catabolism in the liver and is the molecular target of the lipid-lowering fibrates (e.g. fenofibrate and gemfibrozil), whereas PPAR{gamma} is essential for adipocyte differentiation and mediates the activity of the insulin-sensitizing thiazolidinediones (e.g. rosiglitazone and pioglitazone). Recent evidence suggests that PPAR{delta} may be important in controlling triglyceride levels by sensing very low-density lipoprotein. Thus, uncovering the regulatory mechanisms and transcriptional targets of the PPARs will continue to provide insight into the pathogenesis of metabolic diseases and, at the same time, offer valuable information for rational drug design.




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W. Kassouf, S. Chintharlapalli, M. Abdelrahim, G. Nelkin, S. Safe, and A. M. Kamat
Inhibition of Bladder Tumor Growth by 1,1-Bis(3'-Indolyl)-1-(p-Substitutedphenyl)Methanes: A New Class of Peroxisome Proliferator-Activated Receptor {gamma} Agonists
Cancer Res., January 1, 2006; 66(1): 412 - 418.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Renal Physiol.Home page
A. K. Berfield, A. Chait, J. F. Oram, R. A. Zager, A. C. Johnson, and C. K. Abrass
IGF-1 induces rat glomerular mesangial cells to accumulate triglyceride
Am J Physiol Renal Physiol, January 1, 2006; 290(1): F138 - F147.
[Abstract] [Full Text] [PDF]

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 J. Lipid Res.Home page
E. A. Hanniman, G. Lambert, T. C. McCarthy, and C. J. Sinal
Loss of functional farnesoid X receptor increases atherosclerotic lesions in apolipoprotein E-deficient mice
J. Lipid Res., December 1, 2005; 46(12): 2595 - 2604.
[Abstract] [Full Text] [PDF]

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 Hum Mol GenetHome page
F. Djouadi, F. Aubey, D. Schlemmer, J.P.N. Ruiter, R.J.A. Wanders, A.W. Strauss, and J. Bastin
Bezafibrate increases very-long-chain acyl-CoA dehydrogenase protein and mRNA expression in deficient fibroblasts and is a potential therapy for fatty acid oxidation disorders
Hum. Mol. Genet., September 15, 2005; 14(18): 2695 - 2703.
[Abstract] [Full Text] [PDF]

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 NEJMHome page
A. I. Shulman and D. J. Mangelsdorf
Retinoid X Receptor Heterodimers in the Metabolic Syndrome
N. Engl. J. Med., August 11, 2005; 353(6): 604 - 615.
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 Mol. Cell. Biol.Home page
E. Compe, P. Drane, C. Laurent, K. Diderich, C. Braun, J. H. J. Hoeijmakers, and J.-M. Egly
Dysregulation of the Peroxisome Proliferator-Activated Receptor Target Genes by XPD Mutations
Mol. Cell. Biol., July 15, 2005; 25(14): 6065 - 6076.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
J. Kim, P. Yang, M. Suraokar, A. L. Sabichi, N. D. Llansa, G. Mendoza, V. Subbarayan, C. J. Logothetis, R. A. Newman, S. M. Lippman, et al.
Suppression of Prostate Tumor Cell Growth by Stromal Cell Prostaglandin D Synthase-Derived Products
Cancer Res., July 15, 2005; 65(14): 6189 - 6198.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
F. Molnar, M. Matilainen, and C. Carlberg
Structural Determinants of the Agonist-independent Association of Human Peroxisome Proliferator-activated Receptors with Coactivators
J. Biol. Chem., July 15, 2005; 280(28): 26543 - 26556.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
H. Sun, I. M. Berquin, and I. J. Edwards
Omega-3 Polyunsaturated Fatty Acids Regulate Syndecan-1 Expression in Human Breast Cancer Cells
Cancer Res., May 15, 2005; 65(10): 4442 - 4447.
[Abstract] [Full Text] [PDF]

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 J. Lipid Res.Home page
J. M. Wallace, M. Schwarz, P. Coward, J. Houze, J. K. Sawyer, K. L. Kelley, A. Chai, and L. L. Rudel
Effects of peroxisome proliferator-activated receptor {alpha}/{delta} agonists on HDL-cholesterol in vervet monkeys
J. Lipid Res., May 1, 2005; 46(5): 1009 - 1016.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
A. Xu, M. C. Lam, K. W. Chan, Y. Wang, J. Zhang, R. L. C. Hoo, J. Y. Xu, B. Chen, W.-S. Chow, A. W. K. Tso, et al.
Angiopoietin-like protein 4 decreases blood glucose and improves glucose tolerance but induces hyperlipidemia and hepatic steatosis in mice
PNAS, April 26, 2005; 102(17): 6086 - 6091.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
M. F. Simon, D. Daviaud, J. P. Pradere, S. Gres, C. Guigne, M. Wabitsch, J. Chun, P. Valet, and J. S. Saulnier-Blache
Lysophosphatidic Acid Inhibits Adipocyte Differentiation via Lysophosphatidic Acid 1 Receptor-dependent Down-regulation of Peroxisome Proliferator-activated Receptor {gamma}2
J. Biol. Chem., April 15, 2005; 280(15): 14656 - 14662.
[Abstract] [Full Text] [PDF]

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 DiabetesHome page
D. K. Kramer, L. Al-Khalili, S. Perrini, J. Skogsberg, P. Wretenberg, K. Kannisto, H. Wallberg-Henriksson, E. Ehrenborg, J. R. Zierath, and A. Krook
Direct Activation of Glucose Transport in Primary Human Myotubes After Activation of Peroxisome Proliferator-Activated Receptor {delta}
Diabetes, April 1, 2005; 54(4): 1157 - 1163.
[Abstract] [Full Text] [PDF]

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 Mol. Pharmacol.Home page
H.-L. Fang, S. C. Strom, H. Cai, C. N. Falany, T. A. Kocarek, and M. Runge-Morris
Regulation of Human Hepatic Hydroxysteroid Sulfotransferase Gene Expression by the Peroxisome Proliferator-Activated Receptor {alpha} Transcription Factor
Mol. Pharmacol., April 1, 2005; 67(4): 1257 - 1267.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
F. Djouadi, F. Aubey, D. Schlemmer, and J. Bastin
Peroxisome Proliferator Activated Receptor {delta} (PPAR{delta}) Agonist But Not PPAR{alpha} Corrects Carnitine Palmitoyl Transferase 2 Deficiency in Human Muscle Cells
J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1791 - 1797.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
L. Julan, H. Guan, J. P. van Beek, and K. Yang
Peroxisome Proliferator-Activated Receptor {delta} Suppresses 11{beta}-Hydroxysteroid Dehydrogenase Type 2 Gene Expression in Human Placental Trophoblast Cells
Endocrinology, March 1, 2005; 146(3): 1482 - 1490.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
S. Lee, D.-K. Lee, E. Choi, and J. W. Lee
Identification of a Functional Vitamin D Response Element in the Murine Insig-2 Promoter and Its Potential Role in the Differentiation of 3T3-L1 Preadipocytes
Mol. Endocrinol., February 1, 2005; 19(2): 399 - 408.
[Abstract] [Full Text] [PDF]

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 J DAIRY SCIHome page
S. A. Balaguer, R. A. Pershing, C. Rodriguez-Sallaberry, W. W. Thatcher, and L. Badinga
Effects of Bovine Somatotropin on Uterine Genes Related to the Prostaglandin Cascade in Lactating Dairy Cows
J Dairy Sci, February 1, 2005; 88(2): 543 - 552.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Endocrinol. Metab.Home page
U. Kintscher and R. E. Law
PPAR{gamma}-mediated insulin sensitization: the importance of fat versus muscle
Am J Physiol Endocrinol Metab, February 1, 2005; 288(2): E287 - E291.
[Abstract] [Full Text] [PDF]

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 CMAJHome page
A. Y.Y. Cheng and I. G. Fantus
Oral antihyperglycemic therapy for type 2 diabetes mellitus
Can. Med. Assoc. J., January 18, 2005; 172(2): 213 - 226.
[Abstract] [Full Text] [PDF]

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 J. Cell Sci.Home page
H. Patel, R. Truant, R. A. Rachubinski, and J. P. Capone
Activity and subcellular compartmentalization of peroxisome proliferator-activated receptor {alpha} are altered by the centrosome-associated protein CAP350
J. Cell Sci., January 1, 2005; 118(1): 175 - 186.
[Abstract] [Full Text] [PDF]

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 CarcinogenesisHome page
T. Hays, I. Rusyn, A. M. Burns, M. J. Kennett, J. M. Ward, F. J. Gonzalez, and J. M. Peters
Role of peroxisome proliferator-activated receptor-{alpha} (PPAR{alpha}) in bezafibrate-induced hepatocarcinogenesis and cholestasis
Carcinogenesis, January 1, 2005; 26(1): 219 - 227.
[Abstract] [Full Text] [PDF]

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 Circ. Res.Home page
P. R. Devchand, O. Ziouzenkova, and J. Plutzky
Oxidative Stress and Peroxisome Proliferator-Activated Receptors: Reversing the Curse?
Circ. Res., December 10, 2004; 95(12): 1137 - 1139.
[Full Text] [PDF]

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 J. Lipid Res.Home page
S. S. T. Lee, W.-Y. Chan, C. K. C. Lo, D. C. C. Wan, D. S. C. Tsang, and W.-T. Cheung
Requirement of PPAR{alpha} in maintaining phospholipid and triacylglycerol homeostasis during energy deprivation
J. Lipid Res., November 1, 2004; 45(11): 2025 - 2037.
[Abstract] [Full Text] [PDF]

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 Toxicol SciHome page
V. E. Richards, B. Chau, M. R. White, and C. A. McQueen
Hepatic Gene Expression and Lipid Homeostasis in C57Bl/6 Mice Exposed to Hydrazine or Acetylhydrazine
Toxicol. Sci., November 1, 2004; 82(1): 318 - 332.
[Abstract] [Full Text] [PDF]

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 J. Am. Soc. Nephrol.Home page
Y. Guan
Peroxisome Proliferator-Activated Receptor Family and Its Relationship to Renal Complications of the Metabolic Syndrome
J. Am. Soc. Nephrol., November 1, 2004; 15(11): 2801 - 2815.
[Abstract] [Full Text] [PDF]

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 Mol. Cell. Biol.Home page
J. M. Huss, I. P. Torra, B. Staels, V. Giguere, and D. P. Kelly
Estrogen-Related Receptor {alpha} Directs Peroxisome Proliferator-Activated Receptor {alpha} Signaling in the Transcriptional Control of Energy Metabolism in Cardiac and Skeletal Muscle
Mol. Cell. Biol., October 15, 2004; 24(20): 9079 - 9091.
[Abstract] [Full Text] [PDF]

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 J. Pharmacol. Exp. Ther.Home page
B. Brunmair, A. Lest, K. Staniek, F. Gras, N. Scharf, M. Roden, H. Nohl, W. Waldhausl, and C. Furnsinn
Fenofibrate Impairs Rat Mitochondrial Function by Inhibition of Respiratory Complex I
J. Pharmacol. Exp. Ther., October 1, 2004; 311(1): 109 - 114.
[Abstract] [Full Text] [PDF]

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 Circ. Res.Home page
J. M. Huss and D. P. Kelly
Nuclear Receptor Signaling and Cardiac Energetics
Circ. Res., September 17, 2004; 95(6): 568 - 578.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
S. Chintharlapalli, R. Smith III, I. Samudio, W. Zhang, and S. Safe
1,1-Bis(3'-indolyl)-1-(p-substitutedphenyl)methanes Induce Peroxisome Proliferator-Activated Receptor {gamma}-Mediated Growth Inhibition, Transactivation, and Differentiation Markers in Colon Cancer Cells
Cancer Res., September 1, 2004; 64(17): 5994 - 6001.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
P. Yubero, E. Hondares, M. C. Carmona, M. Rossell, F. J. Gonzalez, R. Iglesias, M. Giralt, and F. Villarroya
The Developmental Regulation of Peroxisome Proliferator-Activated Receptor-{gamma} Coactivator-1{alpha} Expression in the Liver Is Partially Dissociated from the Control of Gluconeogenesis and Lipid Catabolism
Endocrinology, September 1, 2004; 145(9): 4268 - 4277.
[Abstract] [Full Text] [PDF]

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 CirculationHome page
Y. Liu, Y. Zhu, F. Rannou, T.-S. Lee, K. Formentin, L. Zeng, X. Yuan, N. Wang, S. Chien, B. M. Forman, et al.
Laminar Flow Activates Peroxisome Proliferator-Activated Receptor-{gamma} in Vascular Endothelial Cells
Circulation, August 31, 2004; 110(9): 1128 - 1133.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
K. Kitajka, A. J. Sinclair, R. S. Weisinger, H. S. Weisinger, M. Mathai, A. P. Jayasooriya, J. E. Halver, and L. G. Puskas
Effects of dietary omega-3 polyunsaturated fatty acids on brain gene expression
PNAS, July 27, 2004; 101(30): 10931 - 10936.
[Abstract] [Full Text] [PDF]

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 J. Lipid Res.Home page
W. Khovidhunkit, M.-S. Kim, R. A. Memon, J. K. Shigenaga, A. H. Moser, K. R. Feingold, and C. Grunfeld
Thematic review series: The Pathogenesis of Atherosclerosis. Effects of infection and inflammation on lipid and lipoprotein metabolism mechanisms and consequences to the host
J. Lipid Res., July 1, 2004; 45(7): 1169 - 1196.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
Y.-m. Liu, M. Moldes, J.-P. Bastard, E. Bruckert, N. Viguerie, B. Hainque, A. Basdevant, D. Langin, J. Pairault, and K. Clement
Adiponutrin: A New Gene Regulated by Energy Balance in Human Adipose Tissue
J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2684 - 2689.
[Abstract] [Full Text] [PDF]

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 J. Lipid Res.Home page
Y. Shidoji and H. Ogawa
Natural occurrence of cancer-preventive geranylgeranoic acid in medicinal herbs
J. Lipid Res., June 1, 2004; 45(6): 1092 - 1103.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
G. Leonardsson, J. H. Steel, M. Christian, V. Pocock, S. Milligan, J. Bell, P.-W. So, G. Medina-Gomez, A. Vidal-Puig, R. White, et al.
Nuclear receptor corepressor RIP140 regulates fat accumulation
PNAS, June 1, 2004; 101(22): 8437 - 8442.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
C. K. Sung, H. She, S. Xiong, and H. Tsukamoto
Tumor necrosis factor-{alpha} inhibits peroxisome proliferator-activated receptor {gamma} activity at a posttranslational level in hepatic stellate cells
Am J Physiol Gastrointest Liver Physiol, May 1, 2004; 286(5): G722 - G729.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Renal Physiol.Home page
R. Mishra, S. N. Emancipator, C. Miller, T. Kern, and M. S. Simonson
Adipose differentiation-related protein and regulators of lipid homeostasis identified by gene expression profiling in the murine db/db diabetic kidney
Am J Physiol Renal Physiol, May 1, 2004; 286(5): F913 - F921.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
T. Imai, R. Takakuwa, S. Marchand, E. Dentz, J.-M. Bornert, N. Messaddeq, O. Wendling, M. Mark, B. Desvergne, W. Wahli, et al.
Peroxisome proliferator-activated receptor {gamma} is required in mature white and brown adipocytes for their survival in the mouse
PNAS, March 30, 2004; 101(13): 4543 - 4547.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
V. Giusti, M. Suter, C. Verdumo, R. C. Gaillard, P. Burckhardt, and F. P. Pralong
Molecular Determinants of Human Adipose Tissue: Differences between Visceral and Subcutaneous Compartments in Obese Women
J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1379 - 1384.
[Abstract] [Full Text] [PDF]

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 DiabetesHome page
C. Eftychi, J. M.M. Howson, B. J. Barratt, A. Vella, F. Payne, D. J. Smyth, R. C.J. Twells, N. M. Walker, H. E. Rance, E. Tuomilehto-Wolf, et al.
Analysis of the Type 2 Diabetes-Associated Single Nucleotide Polymorphisms in the Genes IRS1, KCNJ11, and PPARG2 in Type 1 Diabetes
Diabetes, March 1, 2004; 53(3): 870 - 873.
[Abstract] [Full Text] [PDF]


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