Horm Metab Res 2003; 35(4): 204-210
DOI: 10.1055/s-2003-39475
Review
© Georg Thieme Verlag Stuttgart · New York

New Insights into How Adipocytes Sense their Triglyceride Stores. Is Cholesterol a Signal?

I.  Dugail1 , S.  Le Lay1 , M.  Varret1 , X.  Le Liepvre1 , G.  Dagher1 , P.  Ferré1
  • 1INSERM U 465, Institut Biomedical des Cordeliers, Paris, France
Further Information

Publication History

Received 1 October 2002

Accepted after Revision 15 November 2002

Publication Date:
02 June 2003 (online)

Abstract

In recent years, our view of adipose tissue has evolved from a passive sink for energy storage to an active tissue producing multiple molecules acting on various tissues in different aspects of energy homeostasis. The production of adipose-derived secretory products is tightly regulated as a function of adipocyte lipid accumulation, but the mechanisms by which fat cells are able to sense the levels of their triglyceride stores still remains largely unknown. This paper reviews new insights into this question taking cholesterol as a potential intracellular signaling molecule.

References

  • 1 Blatt D H, Leonard S W, Traber M G. Vitamin E kinetics and the function of tocopherol regulatory proteins.  Nutrition. 2001;  17 799-805
  • 2 Traber M G, Kayden H J. Tocopherol distribution and intracellular localization in human adipose tissue.  Am J Clin Nutr. 1987;  46 488-495
  • 3 Brouwer D A, van Beek J, Ferwerda H, Brugman A M, van der Klis F R, van der Heiden H J, Muskiet F A. Rat adipose tissue rapidly accumulates and slowly releases an orally-administered high vitamin D dose.  Br J Nutr. 1998;  79 527-532
  • 4 Traber M G, Sokol R J, Ringel S P, Neville H E, Thellman C A, Kayden H J. Lack of tocopherol in peripheral nerves of vitamin E-deficient patients with peripheral neuropathy.  N Engl J Med. 1987;  317 262-265
  • 5 Casal S, Macedo B, Oliveira M B. Simultaneous determination of retinol, beta-carotene and alpha-tocopherol in adipose tissue by high-performance liquid chromatography.  J Chromatogr B Biomed Sci Appl. 2001;  763 1-8
  • 6 Sattler W, Levak-Frank S, Radner H, Kostner G M, Zechner R. Muscle-specific overexpression of lipoprotein lipase in transgenic mice results in increased alpha-tocopherol levels in skeletal muscle.  Biochem J. 1996;  318 (Pt 1) 15-19
  • 7 Machlin L J, Gabriel E. Kinetics of tissue alpha-tocopherol uptake and depletion following administration of high levels of vitamin E.  Ann NY Acad Sci. 1982;  393 48-60
  • 8 Chevrier J, Dewailly E, Ayotte P, Mauriege P, Despres J P, Tremblay A. Body weight loss increases plasma and adipose tissue concentrations of potentially toxic pollutants in obese individuals.  Int J Obes Relat Metab Disord. 2000;  24 1272-1278
  • 9 Hardell L, Fredrikson M, Eriksson M, Hansson M, Rappe C. Adipose tissue concentrations of dioxins and dibenzofurans in patients with malignant lymphoproliferative diseases and in patients without a malignant disease.  Eur J Cancer Prev. 1995;  4 225-229
  • 10 Schreibman P H, Dell R B. Human adipocyte cholesterol. Concentration, localization, synthesis, and turnover.  J Clin Invest. 1975 ;  55 986-993
  • 11 Miettinen T A, Tilvis R S. Cholesterol synthesis and storage in adipose tissue.  Int J Obes. 1981;  5 613-618
  • 12 Acton S L, Scherer P E, Lodish H F, Krieger M. Expression cloning of SR-BI, a CD36-related class B scavenger receptor.  J Biol Chem. 1994;  269 21 003-21 009
  • 13 Kovanen P T, Nikkila E A, Miettinen T A. Regulation of cholesterol synthesis and storage in fat cells.  J Lipid Res. 1975;  16 211-223
  • 14 Tilvis R S, Kovanen P T, Miettinen T A. Release of newly synthesized squalene, methyl sterols and cholesterol from human adipocytes in the presence of lipoproteins.  Scand J Clin Lab Invest. 1978;  38 83-87
  • 15 Prattes S, Horl G, Hammer A, Blaschitz A, Graier W F, Sattler W, Zechner R, Steyrer E. Intracellular distribution and mobilization of unesterified cholesterol in adipocytes: triglyceride droplets are surrounded by cholesterol-rich ER-like surface layer structures.  J Cell Sci. 2000;  113 2977-2989
  • 16 Pol A, Luetterforst R, Lindsay M, Heino S, Ikonen E, Parton R G. A caveolin dominant negative mutant associates with lipid bodies and induces intracellular cholesterol imbalance.  J Cell Biol. 2001;  152 1057-1070
  • 17 Ostermeyer A G, Paci J M, Zeng Y, Lublin D M, Munro S, Brown D A. Accumulation of caveolin in the endoplasmic reticulum redirects the protein to lipid storage droplets.  J Cell Biol. 2001;  152 1071-1078
  • 18 Fujimoto T, Kogo H, Ishiguro K, Tauchi K, Nomura R. Caveolin-2 is targeted to lipid droplets, a new ”membrane domain” in the cell.  J Cell Biol. 2001;  152 1079-1086
  • 19 Krause B R, Hartman A D. Adipose tissue and cholesterol metabolism.  J Lipid Res. 1984;  25 97-110
  • 20 Hartman A D, Krause B R. Dietary and pharmacologic influences on adipocyte cholesterol storage.  In: The adipocyte and obesity: cellular and molecular mechanisms. Angel A, Hollenberg CH, Roncari DA (ed.) 1983: 207-210
  • 21 Oram J F, Lawn R M. ABCA1. The gatekeeper for eliminating excess tissue cholesterol.  J Lipid Res. 2001;  42 1173-1179
  • 22 Luo Y, Tall A R. Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element.  J Clin Invest. 2000;  105 513-520
  • 23 Laffitte B A, Repa J J, Joseph S B, Wilpitz D C, Kast H R, Mangelsdorf D J, Tontonoz P. LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes.  Proc Natl Acad Sci USA. 2001;  98 507-512
  • 24 Oram J F, Lawn R M, Garvin M R, Wade D P. ABCA1 is the cAMP-inducible apolipoprotein receptor that mediates cholesterol secretion from macrophages.  J Biol Chem. 2000;  275 34 508-34 511
  • 25 Do M S, Nam S Y, Hong S E, Kim K W, Duncan J S, Beattie J H, Trayhurn P. Metallothionein gene expression in human adipose tissue from lean and obese subjects.  Horm Metab Res. 2002;  34 348-351
  • 26 Brown M S, Goldstein J L. The SREBP pathway: Regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor.  Cell. 1997;  89 331-340
  • 27 Nohturfft A, Brown M S, Goldstein J L. Topology of SREBP cleavage-activating protein, a polytopic membrane protein with a sterol-sensing domain.  J Biol Chem. 1998;  273 17 243-17 250
  • 28 Nohturfft A, Yabe D, Goldstein J L, Brown M S, Espenshade P J. Regulated step in cholesterol feedback localized to budding of SCAP from ER membranes.  Cell. 2000;  102 315-323
  • 29 Yang T, Espenshade P J, Wright M E, Yabe D, Gong Y, Aebersold R, Goldstein J L, Brown M S. Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER.  Cell. 2002;  110 489-500
  • 30 Hahn P. Cholesterol metabolism in obese mice.  Can J Biochem. 1980;  58 1258-1260
  • 31 Soukas A, Cohen P, Socci N D, Friedman J M. Leptin-specific patterns of gene expression in white adipose tissue.  Genes Dev. 2000;  14 963-980
  • 32 Le Lay S, Krief S, Farnier C, Lefrere I, Le Liepvre X, Bazin R, Ferre P, Dugail I. Cholesterol : A cell size dependent signal which regulates glucose metabolism and gene expression in adipocytes.  J Biol Chem. 2001;  276 16 904-16 910
  • 33 Le Lay S, Boucher J, Rey A, Castan-Laurell I, Krief S, Ferre P, Valet P, Dugail I. Decreased resistin expression in mice with different sensitivities to a high-fat diet.  Biochem Biophys Res Commun. 2001;  289 564-567
  • 34 Boizard M, Le Liepvre X, Lemarchand P, Foufelle F, Ferre P, Dugail I. Obesity-related overexpression of fatty-acid synthase gene in adipose tissue involves sterol regulatory element-binding protein transcription factors.  J Biol Chem. 1998;  273 29 164-29 171
  • 35 Oberkofler H, Fukushima N, Esterbauer H, Krempler F, Patsch W. Sterol regulatory element binding proteins: relationship of adipose tissue gene expression with obesity in humans.  Biochim Biophys Acta. 2002;  1575 75-81
  • 36 Tontonoz P, Kim J B, Graves R A, Spiegelman B M. ADD1: a novel helix-loop-helix transcription factor associated with adipocyte determination and differentiation.  Mol Cell Biol. 1993;  13 4753-4759
  • 37 Kim J B, Sarraf P, Wright M, Yao K M, Mueller E, Solanes G, Lowell B B, Spiegelman B M. Nutritional and insulin regulation of fatty acid synthetase and leptin gene expression through ADD1/SREBP1 - Rapid publication.  J Clin Invest. 1998;  101 1-9
  • 38 Foretz M, Pacot C, Dugail I, Lemarchand P, Guichard C, Le Liepvre X, Berthelier-Lubrano C, Spiegelman B, Kim J B, Ferre P, Foufelle F. ADD1/SREBP-1c is required in the activation of hepatic lipogenic gene expression by glucose.  Mol Cell Biol. 1999;  19 3760-3768
  • 39 Le Lay S, Lefrere I, Trautwein C, Dugail I, Krief S. Insulin and sterol regulatory element binding protein-1C regulation of gene expression in 3T3-L1 adipocytes: Identification of C/EBPbeta as a SREBP-1C target. J Biol Chem 2002 277: 35 625-35 634
  • 40 Storch J, Shulman S L, Kleinfeld A M. Plasma membrane lipid order and composition during adipocyte differentiation of 3T3F442A cells. Studies in intact cells with 1-[4-(trimethylamino)phenyl]-6-phenylhexatriene.  J Biol Chem. 1989;  264 10 527-10 533
  • 41 Guerre-Millo M, Guesnet P, Guichard C, Durand G, Lavau M. Alteration in membrane lipid order and composition in metabolically hyperactive Fatty rat adipocytes.  Lipids. 1994;  29 205-209
  • 42 Simons K, Ikonen E. Functionnal rafts in cell membranes.  Nature. 1997;  387 569-572
  • 43 Scherer P E, Lisanti M P, Baldini G, Sargiacomo M, Mastick C C, Lodish H F. Induction of caveolin during adipogenesis and association of GLUT4 with caveolin-rich vesicles.  J Cell Biol. 1994;  127 1233-1243
  • 44 Fernandez I, Ying Y, Albanesi J, Anderson R G. Mechanism of caveolin filament assembly.  Proc Natl Acad Sci USA. 2002;  99 11 193-11 198
  • 45 Li S, Couet J, Lisanti M P. Src tyrosine kinases, Galpha subunits, and H-Ras share a common membrane-anchored scaffolding protein, caveolin. Caveolin binding negatively regulates the auto-activation of Src tyrosine kinases.  J Biol Chem. 1996;  271 29 182-29 190
  • 46 Muller G, Jung C, Wied S, Welte S, Jordan H, Frick W. Redistribution of glycolipid raft domain components induces insulin-mimetic signaling in rat adipocytes.  Mol Cell Biol. 2001;  21 4553-4567
  • 47 Gustavsson J, Parpal S, Karlsson M, Ramsing C, Thorn H, Borg M, Lindroth M, Peterson K H, Magnusson K E, Stralfors P. Localization of the insulin receptor in caveolae of adipocyte plasma membrane.  FASEB J. 1999;  13 1961-1971
  • 48 Rothblat G H, Llera-Moya M, Atger V, Kellner-Weibel G, Williams D L, Phillips M C. Cell cholesterol efflux: integration of old and new observations provides new insights.  J Lipid Res. 1999;  40 781-796
  • 49 Parpal S, Karlsson M, Thorn H, Stralfors P. Cholesterol depletion disrupts caveolae and insulin receptor signaling for metabolic control via IRS-1, but not for MAP-kinase control. J Biol Chem 2001 276: 9670-9678
  • 50 Kim J B, Spotts G, Halvorsen Y D, Shih H M, Ellenberger T, Towle H C, Spiegelman B M. Dual DNA binding specificity of ADD1/SREBP1 controlled by a single amino acid in the basic Helix-Loop-Helix Domain.  Mol Cell Biol. 1998;  15 2582-2588
  • 51 Horton J D, Shimomura I, Brown M S, Hammer R E, Goldstein J L, Shimano H. Activation of cholesterol synthesis in preference to fatty acid synthesis in liver and adipose tissue of transgenic mice overproducing sterol regulatory element-binding protein-2.  J Clin Invest. 1998;  101 2331-2339
  • 52 Hotamisligil G S, Shargill N S, Spiegelman B M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance.  Science. 1993;  259 87-91
  • 53 Fried S K, Bunkin D A, Greenberg A S. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid.  J Clin Endocrinol Metab. 1998;  83 847-850
  • 54 Frederich R C, Kahn B B, Peach M J, Flier J S. Tissue-specific nutritional regulation of angiotensinogen in adipose tissue.  Hypertension. 1992;  19 339-344
  • 55 Van H V, Ariapart P, Hoffstedt J, Lundkvist I, Bringman S, Arner P. Increased adipose angiotensinogen gene expression in human obesity.  Obes Res. 2000;  8 337-341
  • 56 Bennett M K, Osborne T F. Nutrient regulation of gene expression by the sterol regulatory element binding proteins: Increased recruitment of gene-specific coregulatory factors and selective hyperacetylation of histone H3 in vivo.  Proc Natl Acad Sci USA. 2000;  97 6340-6344
  • 57 Kahn B B, Flier J S. Obesity and insulin resistance.  J Clin Invest. 2000;  106 473-481
  • 58 Abel E D, Peroni O D, Kim J K, Kim Y B, Boss O, Hadro E, Minnemann T, Shulman G I, Kahn B B. Adipose-selective targetting of the GLUT4 gene impairs insulin action in muscle and liver.  Nature. 2001;  409 729-733
  • 59 Ai M, Tanaka A, Tomie N, Ogita K, Sekine M, Numano F, Numano F. Triglyceride-rich lipoprotein cholesterol exceeds low-density lipoprotein cholesterol in hypertriglyceridemia patients.  Horm Metab Res. 2001;  33 612-617

I. Dugail

INSERM U 465 · Institut Biomedical des Cordeliers

15, rue de l'école de médecine · 75006 Paris

Phone: +33 (1) 42 23 94 76

Fax: +33 (1) 40 51 85 86

Email: idugail@bhdc.jussieu.fr