Advertisement
Journal of Biological Chemistry
Open access logo
Advanced SearchSave search
MEMBRANE TRANSPORT STRUCTURE FUNCTION AND BIOGENESIS| Volume 277, ISSUE 31, P28182-28190, August 02, 2002

Luminal Leptin Enhances CD147/MCT-1-mediated Uptake of Butyrate in the Human Intestinal Cell Line Caco2-BBE*

Open AccessPublished:May 28, 2002DOI:https://doi.org/10.1074/jbc.M203281200
Luminal Leptin Enhances CD147/MCT-1-mediated Uptake of Butyrate in the Human Intestinal Cell Line Caco2-BBE*
Previous ArticleMucus Secretion from Single Submucosal Glands of Pig
Next ArticleBLOC-1, a Novel Complex Containing the Pallidin and Muted Proteins Involved in the Biogenesis of Melanosomes and Platelet-dense Granules *
      In the intestine, butyrate constitutes the major energy fuel for colonocytes. However, little is known about the transport of butyrate and its regulation in the intestine. In this study we demonstrate that the monocarboxylate transporter (MCT-1) is apically polarized in model human intestinal epithelia and is involved in butyrate uptake by Caco2-BBE cell monolayers. The butyrate uptake by Caco2-BBE cell monolayers displayed conventional Michaelis-Menten kinetics and was found to be pH-dependent, Na+-independent, 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid-insensitive, and inhibited by the monocarboxylate transporter inhibitor α-cyano-4-hydroxycinnamate and by an excess of unlabeled butyrate. We show that MCT-1 associates with CD147 at the apical plasma membrane in Caco2-BBE cell monolayers. Using antisense CD147, we demonstrate that the association of CD147 with MCT-1 is critical for the butyrate transport activity. Interestingly, we show for the first time hormonal regulation of CD147/MCT-1 mediated butyrate uptake. Specifically, luminal leptin significantly up-regulates MCT-1-mediated butyrate uptake by increasing its maximal velocity (V max) without any modification in the apparent Michaelis-Menten constant (K m ). Finally, we show that luminal leptin up-regulates butyrate uptake in Caco2-BBE monolayers by two distinct actions: (i) increase of the intracellular pool of MCT-1 protein without affecting CD147 expression and (ii) translocation of CD147/MCT-1 to the apical plasma membrane of Caco2-BBE cell monolayers.
      SCFA
      short chain fatty acid
      DIDS
      4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid
      MCT
      monocarboxylate transporter
      CHC
      α-cyano-3-hydroxycinnamate
      PBS
      phosphate-buffered saline
      apo
      apolipoprotein
      HBSS
      Hanks' balanced salt solution
      MES
      4-morpholineethanesulfonic acid
      BSA
      bovine serum albumin
      Bacterial fermentation is high in the proximal large bowel, as is the production of short chain fatty acids (SCFA)1 that constitute the major end product of the microbial digestion of carbohydrates and dietary fibers (
      • Topping D.L.
      • Clifton P.M.
      Physiol. Rev. 2001; 8: 11031-11064
      ). At least 60% of SCFA uptake occurs by simple diffusion of the unionized form across the cell membrane; the remainder occurs by active cellular uptake of ionized SCFA involving an acid microclimate on the surface of the intestinal epithelium. SCFA are metabolized rapidly by colonocytes and are the major respiratory fuels in the intestine; indeed, oxidation of SCFA supplies 60–70% of the energy needs in isolated colonocytes (
      • Roediger W.E.
      • Millard S.
      Gut. 1996; 38: 792-793
      ). Of the three major SCFA (acetate, propionate, and butyrate), butyrate is the major intestinal fuel even when competing substrates such as glucose and glutamine are available (
      • Fleming S.E.
      • Fitch M., D.
      • DeVries S.
      • Liu M.L.
      • Kight C.
      J. Nutr. 1991; 121: 869-878
      ,
      • Clausen M.R.
      • Mortensen P.B.
      Gastroenterology. 1994; 106: 423-432
      ,
      • Roediger W.E.
      • Rae D.A.
      Br. J. Surg. 1982; 69: 23-25
      ). Apart from its function as the dominant energy source for the colonocytes, butyrate also affects cellular proliferation, differentiation, and apoptosis (
      • Scheppach W.
      • Christl S., U.
      • Bartram H.P.
      • Richter F.
      • Kasper H.
      Scand. J. Gastroenterol. Suppl. 1997; 222: 53-57
      ,
      • Augeron C.
      • Laboisse C.L.
      Cancer Res. 1984; 44: 3961-3969
      ,
      • McIntyre A.
      • Gibson P.R.
      • Young G.P.
      Gut. 1993; 34: 386-391
      ,
      • Gamet L.
      • Daviaud D.
      • Denis-Pouxviel C.
      • Remesy C.
      • Murat J.C.
      Int. J. Cancer. 1992; 52: 286-289
      ,
      • Siavoshian S.
      • Blottiere H.M.
      • Bentouimou N.
      • Cherbut C.
      • Galmiche J.P.
      Eur J. Clin. Invest. 1996; 26: 803-810
      ).
      Recently, it has been suggested that the proton-linked monocarboxylate transporter 1 (MCT-1) may play a major role in the uptake of butyrate by the intestinal epithelial cells in vivo (
      • Ritzhaupt A.
      • Ellis A.
      • Hosie K.B.
      • Shirazi-Beechey S.P.
      J. Physiol. 1998; 507: 819-830
      ,
      • Ritzhaupt A.
      • Wood I.S.
      • Ellis A.
      • Hosie K.B.
      • Shirazi-Beechey S.P.
      Biochem. Soc. Trans. 1998; 26: S120
      ) as well as in vitro in Caco2 cells (
      • Hadjiagapiou C.
      • Schmidt L.
      • Dudeja P.K.
      • Layden T.J.
      • Ramaswamy K.
      Am. J. Physiol. 2000; 279: G775-G780
      ,
      • Stein J.
      • Zores M.
      • Schroder O.
      Eur. J. Nutr. 2000; 39: 121-125
      ). MCT-1 belongs to the monocarboxylate transporter family including nine MCT-related sequences that have been so far identified in mammals, each having a different tissue distribution (
      • Halestrap A.P.
      • Price N.T.
      Biochem. J. 1999; 343: 281-299
      ). Hydropathy plots predict the number of transmembrane domains to be 12 for MCT-1 with the N and C termini located within the cytoplasm (
      • Price N.T.
      • Jackson V.N.
      • Halestrap A.P.
      Biochem. J. 1998; 329: 321-328
      ). MCT-1 can transport a wide range of short chain monocarboxylates, the K m values (5–10 mm) decreasing as the chain length increases from two to four carbon atoms. Monocarboxylates with longer branched aliphatic or aromatic side chains also bind to the transporter, but are not released following translocation and may act as potent inhibitors. One of these is the classical inhibitor, α-cyano-3-hydroxycinnamate (CHC) (
      • Halestrap A.P.
      • Brand M.D.
      • Denton R.M.
      Biochim. Biophys. Acta. 1974; 367: 102-108
      ). MCT-1 (and MCT-4) has been shown to interact specially with CD147, a member of the immunoglobulin superfamily. This interaction appears to assist MCT expression at the cell surface in heart cells and transfected cells; thus, CD147 acts as a chaperone to increase MCT-1 translocation from the endoplasmic reticulum to the Golgi and plasma membrane (
      • Kirk P.
      • Wilson M.C.
      • Heddle C.
      • Brown M.
      • Barclay H.
      • Halestrap A.P.
      EMBO J. 2000; 19: 3896-3904
      ,
      • Wilson M.C.
      • Meredith D.
      • Halestrap A.P.
      J. Biol. Chem. 2002; 277: 3666-3672
      ,
      • Poole R.C.
      • Halestrap A.P.
      J. Biol. Chem. 1997; 272: 14624-14628
      ). Although the regulation of MCT-1 expression has been extensively studied in skeletal muscle (
      • Hajduch E.
      • Heyes R.R.
      • Watt P.W.
      • Hundal H.S.
      FEBS Lett. 2000; 479: 89-92
      ,
      • Pilegaard H.
      • Juel C.
      • Wibrand F.
      Am. J. Physiol. 1993; 264: E156-E160
      ,
      • Pilegaard H.
      • Domino K.
      • Noland T.
      • Juel C.
      • Hellsten Y.
      • Halestrap A.P.
      • Bangsbo J.
      Am. J. Physiol. 1999; 276: E255-E261
      ,
      • Juel C.
      • Halestrap A.P.
      J. Physiol. 1999; 517: 633-642
      ,
      • McCullagh K.J.
      • Poole R.C.
      • Halestrap A.P.
      • Tipton K.F.
      • O'Brien M.
      • Bonen A.
      Am. J. Physiol. 1997; 273: E239-E246
      ), little is known about the regulation of MCT-1 or its association with CD147 in the intestine.
      Leptin, the ob gene cloned in 1994 by Zhang et al. (
      • Zhang Y.
      • Proenca R.
      • Maffei M.
      • Barone M.
      • Leopold L.
      • Friedman J.M.
      Nature. 1994; 372: 425-432
      ), is a hormone mainly secreted by adipocytes and is involved in central regulation of body weight homeostasis (
      • Halaas J.L.
      • Gajiwala K.S.
      • Maffei M.
      • Cohen S.L.
      • Chait B.T.
      • Rabinowitz D.
      • Lallone R.L.
      • Burley S.K.
      • Friedman J.M.
      Science. 1995; 269: 543-546
      ,
      • Campfield L.A.
      • Smith F.J.
      • Guisez Y.
      • Devos R.
      • Burn P.
      Science. 1995; 269: 546-549
      ,
      • Pelleymounter M.A.
      • Cullen M.J.
      • Baker M.B.
      • Hecht R.
      • Winters D.
      • Boone T.
      • Collins F.
      Science. 1995; 269: 540-543
      ) via its specific receptors in the hypothalamus (
      • Couce M.E.
      • Burguera B.
      • Parisi J.E.
      • Jensen M.D.
      • Lloyd R.V.
      Neuroendocrinology. 1997; 66: 145-150
      ). Subsequent studies have established that nonadipose tissues, such skeletal muscle (
      • Wang X.
      • Levi A.J.
      • Halestrap A.P.
      Am. J. Physiol. 1996; 270: H476-H484
      ), pituitary gland (
      • Jin L.
      • Zhang S.
      • Burguera B.G.
      • Couce M.E.
      • Osamura R.Y.
      • Kulig E.
      • Lloyd R.V.
      Endocrinology. 2000; 141: 333-339
      ), and stomach (
      • Bado A.
      • Levasseur S.
      • Attoub S.
      • Kermorgant S.
      • Laigneau J.P.
      • Bortoluzzi M.N.
      • Moizo L.
      • Lehy T.
      • Guerre-Millo M., Le
      • Marchand-Brustel Y.
      • Lewin M.J.
      Nature. 1998; 394: 790-793
      ) also produce luminal leptin in the nanomolar range as concentration (
      • Bado A.
      • Levasseur S.
      • Attoub S.
      • Kermorgant S.
      • Laigneau J.P.
      • Bortoluzzi M.N.
      • Moizo L.
      • Lehy T.
      • Guerre-Millo M., Le
      • Marchand-Brustel Y.
      • Lewin M.J.
      Nature. 1998; 394: 790-793
      ,
      • Sobhani I.
      • Bado A.
      • Vissuzaine C.
      • Buyse M.
      • Kermorgant S.
      • Laigneau J.P.
      • Attoub S.
      • Lehy T.
      • Henin D.
      • Mignon M.
      • Lewin M.J.
      Gut. 2000; 47: 178-183
      ). Moreover under secretin, pentagastrin, or vagal stimulation, the gastric luminal leptin output increased by ∼50 times (
      • Sobhani I.
      • Bado A.
      • Vissuzaine C.
      • Buyse M.
      • Kermorgant S.
      • Laigneau J.P.
      • Attoub S.
      • Lehy T.
      • Henin D.
      • Mignon M.
      • Lewin M.J.
      Gut. 2000; 47: 178-183
      ,
      • Sobhani I.
      • Buyse M.
      • Goiot H.
      • Weber N.
      • Laigneau J.P.
      • Henin D.
      • Soul J.C.
      • Bado A.
      Gastroenterology. 2002; 122: 259-263
      ). In addition, it has been recently demonstrated that some of the stomach-derived leptin secreted in the gastric juice is not fully degraded by proteolysis, suggesting that it reaches the intestine in an active form, and thus can initiate biological processes involved in controlling functions of the intestinal tract, such as absorption and secretion (
      • Sobhani I.
      • Bado A.
      • Vissuzaine C.
      • Buyse M.
      • Kermorgant S.
      • Laigneau J.P.
      • Attoub S.
      • Lehy T.
      • Henin D.
      • Mignon M.
      • Lewin M.J.
      Gut. 2000; 47: 178-183
      ). Recently, we have found that the concentration of luminal leptin from normal colon is in the low nanomolar range. We suggest that this leptin is coming from the gastric gland because no leptin staining was detected from the epithelial cells along normal small and large intestine.
      S. V. Sitaraman and D. Merlin, unpublished observations.
      2S. V. Sitaraman and D. Merlin, unpublished observations.
      Interestingly, under inflammatory states, we have detected a strong leptin staining from colonic epithelial cells and the luminal leptin concentration increased significantly (∼10 times greater compared with noninflamed tissues).2 During inflammation the luminal colonic leptin concentration is likely to be the addition of the leptin produced by the gastric gland and the leptin produced by the colonic epithelial cells. These results suggest that luminal leptin could have an important physiological and/or pathological role in the colon. Indeed, the different leptin receptor isoforms including the functional long isoform (Ob-Rb) have been detected in the rat intestine from duodenum to colon and in the model intestinal cell line Caco2 (
      • Buyse M.
      • Berlioz F.
      • Guilmeau S.
      • Tsocas A.
      • Voisin T.
      • Peranzi G.
      • Merlin D.
      • Laburthe M.
      • Lewin M., J.
      • Roze C.
      • Bado A.
      J. Clin. Invest. 2001; 108: 1483-1494
      ,
      • Lostao M.P.
      • Urdaneta E.
      • Martinez-Anso E.
      • Barber A.
      • Martinez J.A.
      FEBS Lett. 1998; 423: 302-306
      ,
      • Morton N.M.
      • Emilsson V.
      • Liu Y.L.
      • Cawthorne M.A.
      J. Biol. Chem. 1998; 273: 26194-26201
      ,
      • Doi T.
      • Liu M.
      • Seeley R.J.
      • Woods S.C.
      • Tso P.
      Am. J. Physiol. 2001; 281: R753-R759
      ,
      • Stan S.
      • Levy E.
      • Bendayan M.
      • Zoltowska M.
      • Lambert M.
      • Michaud J.
      • Asselin C.
      • Delvin E.E.
      FEBS Lett. 2001; 508: 80-84
      ). The demonstration of leptin receptor in intestinal tract has initiated several investigations on the possible role of leptin in the digestive physiology as absorption and secretion. Evidence has been provided that leptin can regulate intestinal triglyceride transport by inhibiting apolipoprotein AIV expression via activation of a jejunal leptin receptor in mice (
      • Morton N.M.
      • Emilsson V.
      • Liu Y.L.
      • Cawthorne M.A.
      J. Biol. Chem. 1998; 273: 26194-26201
      ). Similarly, in rat, intravenous leptin infusion attenuates the increase in synthesis and secretion of apoAIV induced by intraduodenal infusion of lipids (
      • Doi T.
      • Liu M.
      • Seeley R.J.
      • Woods S.C.
      • Tso P.
      Am. J. Physiol. 2001; 281: R753-R759
      ). In addition, leptin administered to the basolateral side of Caco2 cells inhibits the triglyceride secretion, the biosynthesis of apoB-100 and apoB-48, as well as the output of chylomicron and low density lipoproteins (
      • Stan S.
      • Levy E.
      • Bendayan M.
      • Zoltowska M.
      • Lambert M.
      • Michaud J.
      • Asselin C.
      • Delvin E.E.
      FEBS Lett. 2001; 508: 80-84
      ). More recently, we have reported that luminal leptin improves the transport of oligopeptides across the intestinal epithelium through the H+-dependent, di- and tripeptide transporter PepT-1 in vitro and in vivo (
      • Buyse M.
      • Berlioz F.
      • Guilmeau S.
      • Tsocas A.
      • Voisin T.
      • Peranzi G.
      • Merlin D.
      • Laburthe M.
      • Lewin M., J.
      • Roze C.
      • Bado A.
      J. Clin. Invest. 2001; 108: 1483-1494
      ). Together, the results clearly demonstrate that leptin is a key hormone of the intestinal tract. This study aims to investigate the regulation of butyrate uptake by luminal leptin using the model human intestinal epithelial cell line Caco2-BBE.

      DISCUSSION

      In this study, we demonstrate that MCT-1 is apically polarized in model human intestinal epithelia and is involved in the butyrate uptake by Caco2-BBE cell monolayers. The butyrate uptake by Caco2-BBE cell monolayers is pH-dependent, Na+-independent, DIDS-insensitive, and inhibited by the MCT inhibitor CHC and by an excess of unlabeled butyrate. Together, these results indicate that apical butyrate uptake by Caco2-BBE cell monolayers are mainly the result of a single carrier MCT-1 and are in agreement with previous studies (
      • Hadjiagapiou C.
      • Schmidt L.
      • Dudeja P.K.
      • Layden T.J.
      • Ramaswamy K.
      Am. J. Physiol. 2000; 279: G775-G780
      ). Caco2-BBE at 15 days after plating exhibited partially small intestinal phenotype. However, we found the same butyrate transport characteristics in HT29-Cl.19A (data not shown), which exhibited colonocyte features. Thus, with respect to butyrate uptake studies, Caco2-BBE cells represent an appropriate cellular model.
      In the present study, we bring important information to the field of MCT by providing the first evidence for its stimulation by a hormone. Indeed, luminal leptin significantly increased the maximal velocity (V max) for butyrate uptake, whereas the apparent Michaelis-Menten constant (K m ) did not change. Moreover, the addition of an excess of butyrate or the use of the MCT inhibitor, CHC, suppressed the luminal leptin-induced increase in butyrate uptake. These results demonstrate that the increased of butyrate uptake induced by luminal leptin is mediated by the same transporter (MCT-1) involved in base-line conditions.
      We show that MCT-1 and CD147 are localized to the apical plasma membrane in Caco2-BBE monolayers. Furthermore, we demonstrate that the CD147/MCT-1 association is critical for the butyrate transport activity. The inhibition of butyrate uptake with an antisense construct to CD147 transiently transfected into Caco2-BBE cell monolayers supports the requirement of CD147 in butyrate transport. CD147 protein is probably specifically interacting with MCT-1, because previous studies using MCT-1 antisense show similar inhibition (∼35%) of butyrate uptake by Caco2 monolayers (
      • Hadjiagapiou C.
      • Schmidt L.
      • Dudeja P.K.
      • Layden T.J.
      • Ramaswamy K.
      Am. J. Physiol. 2000; 279: G775-G780
      ). These data are consistent with similar findings in murine heart plasma membrane and in cells co-transfected with CD147 and MCT-1 in which CD147 was reported to facilitate proper expression of MCT-1 at the cell surface, where they remained tightly associated (
      • Kirk P.
      • Wilson M.C.
      • Heddle C.
      • Brown M.
      • Barclay H.
      • Halestrap A.P.
      EMBO J. 2000; 19: 3896-3904
      ,
      • Wilson M.C.
      • Meredith D.
      • Halestrap A.P.
      J. Biol. Chem. 2002; 277: 3666-3672
      ,
      • Poole R.C.
      • Halestrap A.P.
      J. Biol. Chem. 1997; 272: 14624-14628
      ). This interaction has potential significance for the regulation of MCT-1 activity. Proteins acting as a protein chaperone for other transporter have been described. For example, glycophorin associates with the anion exchanger AE1 (
      • Groves J.D.
      • Tanner M.J.A.
      J. Biol. Chem. 1992; 267: 22163-22170
      ,
      • Groves J.D.
      • Tanner M.J.A.
      J. Membr. Biol. 1994; 140: 81-88
      ), CD98 that associates with amino acid transporters (
      • Merlin D.
      • Sitaraman S.
      • Liu X.
      • Eastburn K.
      • Sun J.
      • Kucharzik T.
      • Lewis B.
      • Madara J.L.
      J. Biol. Chem. 2001; 276: 39282-39289
      ,
      • Mastro-Berardino L.
      • Spindler B.
      • Pfeiffer R.
      • Skelly P.J.
      • Loffing J.
      • Shoemaker C.B.
      • Verrey F.
      Nature. 1998; 395: 288-291
      ), or CD36 that associates with the long chain fatty acid transporter (
      • Schaffer J.E.
      • Lodish H.F.
      Cell. 1994; 79: 427-436
      ). All these associations have been shown to be essential for the appropriate function of these transporters.
      Interestingly, we show that luminal leptin increases the total amount of MCT-1 proteins, attributable to a relative increase in expression of MCT-1 mRNA, but did not change the total mRNA or protein level of CD147. Moreover, luminal leptin treatment induced an increase in the number of positive cell for MCT-1 in accordance with the enhancement of protein synthesis. Furthermore we demonstrate, using confocal imaging and by isolating membrane from Caco2-BBE cells, that after luminal treatment CD147 and MCT-1 membrane proteins increase, indicating that CD147 and MCT-1 are translocated to the apical membrane. Based on our observations that the association of MCT-1 and CD147 is crucial for the MCT-1 transport function, the leptin-induced translocation of CD147 to the apical membrane could play a role in the increase of butyrate uptake by leptin.
      Little is known about the regulation of MCT-1 expression in various tissues, but, in skeletal muscles, endurance and high intensity training have been shown to increase the expression of MCT-1 and transport activity (
      • McCullagh K.J.
      • Poole R.C.
      • Halestrap A.P.
      • Tipton K.F.
      • O'Brien M.
      • Bonen A.
      Am. J. Physiol. 1997; 273: E239-E246
      ,
      • McDermott J.C.
      • Bonen A.
      Acta Physiol. Scand. 1993; 147: 323-327
      ). However, to date there is no published promoter analysis for any of the MCT isoforms, and we cannot speculate whether luminal leptin effect involved direct or indirect regulation of MCT-1 gene promoter activity.
      The increase in butyrate uptake in the enterocyte by luminal leptin represents an important issue because butyrate has been shown to present physiological and therapeutic interest. The presence of luminal leptin in the intestinal lumen (
      • Sobhani I.
      • Buyse M.
      • Goiot H.
      • Weber N.
      • Laigneau J.P.
      • Henin D.
      • Soul J.C.
      • Bado A.
      Gastroenterology. 2002; 122: 259-263
      ) could contribute to maintain MCT-1/CD147 membrane expression and thereby regulate intestinal inflammation via butyrate-dependent system in response to changes in the intestinal milieu. The ability of butyrate to induce cancer cell apoptosis may contribute to the cancer preventive activity of SFCA. In the diseased colon, expression of MCT-1 or CD147 protein may be impaired; this in turn would reduce the availability of SCFA required to maintain the intracellular events regulating normal differentiation and proliferation in the colonic mucosa.
      In summary we demonstrate that (i) luminal leptin up-regulates butyrate uptake mediated by MCT-1, (ii) MCT-1 associates with CD147 at the apical membrane and the expression of CD147 is crucial for MCT-1 transport activity, (iii) luminal leptin increases the intracellular pool of MCT-1 protein, and (iv) luminal leptin induces a translocation of CD147/MCT-1 to the apical plasma membrane.

      REFERENCES

        • Topping D.L.
        • Clifton P.M.
        Physiol. Rev. 2001; 8: 11031-11064
        View in Article
        • Roediger W.E.
        • Millard S.
        Gut. 1996; 38: 792-793
        View in Article
        • Fleming S.E.
        • Fitch M., D.
        • DeVries S.
        • Liu M.L.
        • Kight C.
        J. Nutr. 1991; 121: 869-878
        View in Article
        • Clausen M.R.
        • Mortensen P.B.
        Gastroenterology. 1994; 106: 423-432
        View in Article
        • Roediger W.E.
        • Rae D.A.
        Br. J. Surg. 1982; 69: 23-25
        View in Article
        • Scheppach W.
        • Christl S., U.
        • Bartram H.P.
        • Richter F.
        • Kasper H.
        Scand. J. Gastroenterol. Suppl. 1997; 222: 53-57
        View in Article
        • Augeron C.
        • Laboisse C.L.
        Cancer Res. 1984; 44: 3961-3969
        View in Article
        • McIntyre A.
        • Gibson P.R.
        • Young G.P.
        Gut. 1993; 34: 386-391
        View in Article
        • Gamet L.
        • Daviaud D.
        • Denis-Pouxviel C.
        • Remesy C.
        • Murat J.C.
        Int. J. Cancer. 1992; 52: 286-289
        View in Article
        • Siavoshian S.
        • Blottiere H.M.
        • Bentouimou N.
        • Cherbut C.
        • Galmiche J.P.
        Eur J. Clin. Invest. 1996; 26: 803-810
        View in Article
        • Ritzhaupt A.
        • Ellis A.
        • Hosie K.B.
        • Shirazi-Beechey S.P.
        J. Physiol. 1998; 507: 819-830
        View in Article
        • Ritzhaupt A.
        • Wood I.S.
        • Ellis A.
        • Hosie K.B.
        • Shirazi-Beechey S.P.
        Biochem. Soc. Trans. 1998; 26: S120
        View in Article
        • Hadjiagapiou C.
        • Schmidt L.
        • Dudeja P.K.
        • Layden T.J.
        • Ramaswamy K.
        Am. J. Physiol. 2000; 279: G775-G780
        View in Article
        • Stein J.
        • Zores M.
        • Schroder O.
        Eur. J. Nutr. 2000; 39: 121-125
        View in Article
        • Halestrap A.P.
        • Price N.T.
        Biochem. J. 1999; 343: 281-299
        View in Article
        • Price N.T.
        • Jackson V.N.
        • Halestrap A.P.
        Biochem. J. 1998; 329: 321-328
        View in Article
        • Halestrap A.P.
        • Brand M.D.
        • Denton R.M.
        Biochim. Biophys. Acta. 1974; 367: 102-108
        View in Article
        • Kirk P.
        • Wilson M.C.
        • Heddle C.
        • Brown M.
        • Barclay H.
        • Halestrap A.P.
        EMBO J. 2000; 19: 3896-3904
        View in Article
        • Wilson M.C.
        • Meredith D.
        • Halestrap A.P.
        J. Biol. Chem. 2002; 277: 3666-3672
        View in Article
        • Poole R.C.
        • Halestrap A.P.
        J. Biol. Chem. 1997; 272: 14624-14628
        View in Article
        • Hajduch E.
        • Heyes R.R.
        • Watt P.W.
        • Hundal H.S.
        FEBS Lett. 2000; 479: 89-92
        View in Article
        • Pilegaard H.
        • Juel C.
        • Wibrand F.
        Am. J. Physiol. 1993; 264: E156-E160
        View in Article
        • Pilegaard H.
        • Domino K.
        • Noland T.
        • Juel C.
        • Hellsten Y.
        • Halestrap A.P.
        • Bangsbo J.
        Am. J. Physiol. 1999; 276: E255-E261
        View in Article
        • Juel C.
        • Halestrap A.P.
        J. Physiol. 1999; 517: 633-642
        View in Article
        • McCullagh K.J.
        • Poole R.C.
        • Halestrap A.P.
        • Tipton K.F.
        • O'Brien M.
        • Bonen A.
        Am. J. Physiol. 1997; 273: E239-E246
        View in Article
        • Zhang Y.
        • Proenca R.
        • Maffei M.
        • Barone M.
        • Leopold L.
        • Friedman J.M.
        Nature. 1994; 372: 425-432
        View in Article
        • Halaas J.L.
        • Gajiwala K.S.
        • Maffei M.
        • Cohen S.L.
        • Chait B.T.
        • Rabinowitz D.
        • Lallone R.L.
        • Burley S.K.
        • Friedman J.M.
        Science. 1995; 269: 543-546
        View in Article
        • Campfield L.A.
        • Smith F.J.
        • Guisez Y.
        • Devos R.
        • Burn P.
        Science. 1995; 269: 546-549
        View in Article
        • Pelleymounter M.A.
        • Cullen M.J.
        • Baker M.B.
        • Hecht R.
        • Winters D.
        • Boone T.
        • Collins F.
        Science. 1995; 269: 540-543
        View in Article
        • Couce M.E.
        • Burguera B.
        • Parisi J.E.
        • Jensen M.D.
        • Lloyd R.V.
        Neuroendocrinology. 1997; 66: 145-150
        View in Article
        • Wang X.
        • Levi A.J.
        • Halestrap A.P.
        Am. J. Physiol. 1996; 270: H476-H484
        View in Article
        • Jin L.
        • Zhang S.
        • Burguera B.G.
        • Couce M.E.
        • Osamura R.Y.
        • Kulig E.
        • Lloyd R.V.
        Endocrinology. 2000; 141: 333-339
        View in Article
        • Bado A.
        • Levasseur S.
        • Attoub S.
        • Kermorgant S.
        • Laigneau J.P.
        • Bortoluzzi M.N.
        • Moizo L.
        • Lehy T.
        • Guerre-Millo M., Le
        • Marchand-Brustel Y.
        • Lewin M.J.
        Nature. 1998; 394: 790-793
        View in Article
        • Sobhani I.
        • Bado A.
        • Vissuzaine C.
        • Buyse M.
        • Kermorgant S.
        • Laigneau J.P.
        • Attoub S.
        • Lehy T.
        • Henin D.
        • Mignon M.
        • Lewin M.J.
        Gut. 2000; 47: 178-183
        View in Article
        • Sobhani I.
        • Buyse M.
        • Goiot H.
        • Weber N.
        • Laigneau J.P.
        • Henin D.
        • Soul J.C.
        • Bado A.
        Gastroenterology. 2002; 122: 259-263
        View in Article
        • Buyse M.
        • Berlioz F.
        • Guilmeau S.
        • Tsocas A.
        • Voisin T.
        • Peranzi G.
        • Merlin D.
        • Laburthe M.
        • Lewin M., J.
        • Roze C.
        • Bado A.
        J. Clin. Invest. 2001; 108: 1483-1494
        View in Article
        • Lostao M.P.
        • Urdaneta E.
        • Martinez-Anso E.
        • Barber A.
        • Martinez J.A.
        FEBS Lett. 1998; 423: 302-306
        View in Article
        • Morton N.M.
        • Emilsson V.
        • Liu Y.L.
        • Cawthorne M.A.
        J. Biol. Chem. 1998; 273: 26194-26201
        View in Article
        • Doi T.
        • Liu M.
        • Seeley R.J.
        • Woods S.C.
        • Tso P.
        Am. J. Physiol. 2001; 281: R753-R759
        View in Article
        • Stan S.
        • Levy E.
        • Bendayan M.
        • Zoltowska M.
        • Lambert M.
        • Michaud J.
        • Asselin C.
        • Delvin E.E.
        FEBS Lett. 2001; 508: 80-84
        View in Article
        • Merlin D., Si-
        • Tahar M.
        • Sitaraman S.V.
        • Eastburn K.
        • Williams I.
        • Liu X.
        • Hediger M.A.
        • Madara J.L.
        Gastroenterology. 2001; 120: 1666-1679
        View in Article
        • Groves J.D.
        • Tanner M.J.A.
        J. Biol. Chem. 1992; 267: 22163-22170
        View in Article
        • Groves J.D.
        • Tanner M.J.A.
        J. Membr. Biol. 1994; 140: 81-88
        View in Article
        • Merlin D.
        • Sitaraman S.
        • Liu X.
        • Eastburn K.
        • Sun J.
        • Kucharzik T.
        • Lewis B.
        • Madara J.L.
        J. Biol. Chem. 2001; 276: 39282-39289
        View in Article
        • Mastro-Berardino L.
        • Spindler B.
        • Pfeiffer R.
        • Skelly P.J.
        • Loffing J.
        • Shoemaker C.B.
        • Verrey F.
        Nature. 1998; 395: 288-291
        View in Article
        • Schaffer J.E.
        • Lodish H.F.
        Cell. 1994; 79: 427-436
        View in Article
        • McDermott J.C.
        • Bonen A.
        Acta Physiol. Scand. 1993; 147: 323-327
        View in Article

      Article Info

      Publication History

      Published online: May 28, 2002
      Received in revised form: May 28, 2002
      Received: April 5, 2002

      Footnotes

      Published, JBC Papers in Press, May 28, 2002, DOI 10.1074/jbc.M203281200

      Identification

      DOI: https://doi.org/10.1074/jbc.M203281200

      Copyright

      © 2002 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.

      User License

      Creative Commons Attribution (CC BY 4.0) |
      How you can reuse Information Icon
      Creative Commons Attribution (CC BY 4.0)

      Permitted

      • Read, print & download
      • Redistribute or republish the final article
      • Text & data mine
      • Translate the article
      • Reuse portions or extracts from the article in other works
      • Sell or re-use for commercial purposes

      Elsevier's open access license policy

      ScienceDirect

      Access this article on ScienceDirect

      ASBMB  ASBMB  ASBMB  ASBMB

      ISSN 0021-9258
      We use cookies to help provide and enhance our service and tailor content. To update your cookie settings, please visit the for this site.
      Copyright © 2022 Elsevier Inc. except certain content provided by third parties. The content on this site is intended for healthcare professionals.


      RELX