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4. Diynan L, Quant PA arad Zaminir VA, Flux control exerted by mitochondrial outer membrana carnirine palmitoyltransferase ovar 13-oxidatiora, kctogenesis arad tricarboxylic acid cycle activity ira hepatocytas isolated from rats ira differarar metabolic states. Biochem J 317: 791-795, 1996. 5. Spurway T, Sberrat HSA, Pagsara CI arad Agius 1., The flux control coefflcierat of camitine palmilioyltrarasferasa 1 ora palmitate 13-oxidation ira rat bepatacyta cultures. Biochem J 323: 119-122, 1997. 6. Guzmán M. arad Castro J, Okadaic acid stimulates carraitine palmitoyltransferase 1 activity arad palmitate oxidation in isolated rat hepatocytes. FEES Lea 291: 105-108, 1991. 7. Guzmán M arad Geelera MJH, Acdvity of carnitine palmiroyltransferase in mitochoradrial auter membranas arad peroxisomes ira digitonira-panraeabilizad hapatocytes.’ Salective modulation of mitochondrial enzyma activiry by okadaic acid. Biochem J 287: 487-492, ‘1992. 8. Guzmán M, Kolodziej MP, Caldwell A, Costorphine CG arad Zamniit VA, Evideraca against direel iravolvemerat of phosphorylation ira tbe activation of carnitine palmitoyltransfarase by okadaic acid ira rat hapatocylies. Biochem J 300: 693-699, 1994. 9. Velasco O, Sánchez C, Gaelara MJH arad Guzmán M, Are cytaskaletal comporaeralis iravolved in the control of bepatic carraitine palmitayltrarasferase 1 activity? Biochem Biophys Res Commun 224: 754- 759, 1996. 10. Velasco G, Guzmán M, Zammit VA arad Geelan MJH, Iravolvement of Ca 2jcalmodulira-deperaderat protein kiraasa II ira the activadora of carraitina palmitoyltrarasferase 1 by okadaic acid ira rat bepatocylies. Biochem J 321: 211-216, 1997. 11. Passilly P, Jannin B and Latruffe N, Influance ofperoxisame proliferators an phospboproteira leveis ira human arad hepatic-darived ccli unes. Eur J Biochem 230: 3 16-321, 1995. 12. Prip-Buus C, Bouthillier-Voisin AC, Kohl C, Demaugra F, Girard J arad Pegoriar JP, Evidarace for ara impaired long-chaira fatty acid oxidatiora arad ketagaraasis in Fao bepatoma calis. Eta J Biochem 209: 291-298, 1992. 13. Dixon JL arad Girasberg HN, Regulation of heparic sectadora of apolipoprotein B-contairairag lipoproteiras: inforination obtairaed from cultured liver celis. J Lipid Res 34: 167-179, 1993. 14. Ducías 5, Bride J, Ramiraz LC arad Baurnor P, Proxisome proliferatiora arad beta-oxidatiora ira Fao arad MH1C1 rat hepatoma celís, HapG2 human bepatoblastoma calis arad culturad human bepatocytes: effect of cipofibrate. EurJ Ccli Biol 72: 314-323, 1997. 15. Halan 1, Gordon PB arad Saglen PO, Proteira kiraasa-depanderat affedts ofokadaic acid ora hapatocytic autophagy arad cyliaskeletal iratagrity. Biochem J 284: 633-636, 1992. 16. Gurlarad G arad Guradarsara GO, Proteira phospbatasa irahibitors induce libe selectiva breakdown of stable microtubules ira fibrablaslis arad epilihelial calís. Proc Nos) Acad Sc) USA 90: 8827-8831, 1993. 17. Collier NC, Sbeerz MP arad Scblesiragar MJ, Coraeamirant changas ira mirochoradria arad intermediare filamaralis durirag bear shock arad recovar>’ of chickara ambryo fibroblasts.J Ccli Biochem 52: 297-307, 1993.
ARCHIVES OF BIOCHEMJSTRY AND BIOPHYSICS Vol. 337. No. 2, January 15, pp. 169—175, 1997 Article No. BB969784 Control of Hepatio Fatty Acid Oxidation by 5’—AMP- Activated Protein Kinase Involves a Malonyl-CoA- Dependent and a Malonyl-CoA-Independent Mechanism Guillermo Velasco,* Math J. H. Geelen,t” arad Manuel Guzmán* *Department of Biochemistry and Molecular Biology 1, Faculty of Biology, Complutense University, 28040-Madrid, Spain; aná tLaboratory of Veterinary Biochemistry, Graduate School of Animal Health, Utreche Uniuersity, PO. Box 80.176, 3508 TD Utreeht, Tite Netherlands Received July 30, 1996, and in revised fon,, October 25, 1996 Incubation of rat hepatocytes with 5-aminoimidazo¡e-4-carboxamide ribonucleoside (AICAR), aix activaliar of the 5’-AM?P-activated protein kinase (AMPK), produced a twofoíd stimuíation of palmitate oxidation arad of the activity of carnitine pahnitoyltransferase 1 (CPT-I), together with a profonrad decrease of the activity of acetyí-CoA carboxyíase arad of lihe iratracellular level of malorayí-CoA. AICAR-induced CPT-I stimulation progressively blunted with time after ccli permeabilization, pointing to reversal of conformational eonstraints of the enzyme ira control celis due to the permeabilizatiora-triggered dilution of intracelular malonyl-CoA. The stimulation stabilized at a steady 20—25%. This 20—25% mercase ira CPT-I activity survived upon complete removal of malonyl-CaA from the permeabilized celís, indicating that it was not dependent on the malonyí-CoA concentration oflibe eclI. This malonyl-CoA-indcpendeixt activatiora of CPT-I was not cvident wheix mitochondria wcre isolated for assay of enzyme activity or when celís were disrupted by vigoraus sonication. lix addition, libe microtubule stabilizcr taxol prevented lihe malonyí-CoA-independent stimulation of CPT-I induced by AICAR. Henee, stimuíation of hepatic fatty acid oxidatiora by AMPK seems to rely on lihe activation of CPT-I by two different mechanisms: deinhibition of CPT-I induced by depíetion of intracellular maíonyl-CoA leveís and maíonyl-CoA-iradcpendent stimulation of CPT-I, which might involve modulation of interaetioras between CPT-I arad cytoskelctal Components. o 1997 Academie Press To whom correspondence should be addressed. Fax: **3130 2535492. E-mail: m.geelen~biochemdgk.niunl. 0003-9861,97 $2500 Copyright 0 1997 by Academic Presa MI rights of reproduction jo any form reserved. The 5’-AMP-activated proteira kinase (AMPK? plays a majar role ira tbe regulatiora of lipid metabolism ira mammals. Thus, AMPK pbospborylates and inactivates key regulatory enzymes of lipid metabolism such as aeetyl-CoA carboxylase (fatty acid syratbesis), 3-hydroxy-S-methylglutaryl-CoA reductase (sterol/isopreraoid syratbesis), arad bormone-serasitive lipase (triacylglycerol/cholesteryl ester breakdowra) [reviewed ira Ref. (1)]. Although several protein kinases cara pbospborylate purified acetyl-CoA earboxylase arad S-hydroxy-3metbylglutaryl-CoA reductase in vitro, it is curreratly accepted thaI ira iratact hepatocytes arad ira the liver in vivo this phosphorylation. is mairaly performed by AMPK [cf. Refs. (1—3)]. Several studies have beera performed ora the potential involvemerat ofAMPK ira Ibe control offatty acid oxidatiora ira the isehemié beart (4, 5) arad the workirag muscle (6). However, the possible role of this kiraase ira tbe control of hepatie fatty acid oxidation has raot beera studied to date. Uralike tbe beart arad the skeletal muscíe, the liver is capable of expressirag eitber bigh rates of lipogeraesis or higb rates of fatty acid oxidatiora deperadirag on Ihe hormonal arad rautritional status of the animal, arad herace regulatiora of fatty acid axidatiora seems to be more complex ira liver [reviewed ira Ref. (7)] than ira heart [reviewed ira Ref. (8)] arad skeletal niuscle [reviewed ira Ref. (9)]. Carnitine palmitoyltrarasferase 1 (CPT-I) is the key regulatory erazyme ira the trarasport of long-chaira fatty acids irato the mitochoradrial matrix (7, 10, 11). This enzyme is subject to allosterie inhibition by malorayl-CoA, the produet of the reactiora caía- 2 Ahbreviations used: AMPK, 5’-AMP-activated protein kinnse: CoA, coenzyme A: CPT-I, carnitine palmitoyltransferase 1; AICAR, 5-aminoimidazote-4-carboxamide ribonucleoside; ZMP, 5-aminoin,idazole-4-carboxamide ribonucleoside monophosphate. 169
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UNiVERSIDAD COMPLUTENSE DE MADRID F
Page 3 and 4:
1. INTRODUCCIÓN ÍNDICE 1.1. ASPEC
Page 5 and 6:
L Introducción
Page 7 and 8:
Canítulo 1 Introducción en forma
Page 9 and 10:
Can/tu/o ¡ 1988) y sales biliares
Page 11 and 12:
Capítulo 1 Introducción sistema d
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Capitulo 1 Introducción ble la sí
Page 15 and 16:
Can¡tu/o 1 introducción Ca racten
Page 17 and 18:
Cadhulo 1 Introducción drial exter
Page 19 and 20:
Canítulo 1 Introduccián del malon
Page 21 and 22: Capitulo ¡ Introducción Preincuba
Page 23 and 24: Canítulo ¡ BIBLIOGRAFLA Abunirad,
Page 25 and 26: Capítulo ¡ Rodríguez, J.C., Cil-
Page 27 and 28: 2.1. Efectos deJATP extracelulary d
Page 29 and 30: Effects of extracellular ATP Qn hep
Page 31 and 32: Tabla 1. Effect of extracellular A=
Page 33 and 34: EFFECTS OF EXTRACEI 4LULARATP Di HE
Page 35 and 36: EFFECTS OF EXTRACELLTJLAR AIF Di HE
Page 37 and 38: 240 snspansions ware incubatad at 3
Page 39 and 40: Capitulo 2 Bibliograria. DISCUSIÓN
Page 41 and 42: Capitulo 2 INTRODUCCIÓN Resultados
Page 43 and 44: BIOCHEMICAL AND B!OPHYSTCAL RESEARC
Page 45 and 46: Vol. 224, No. 3, 1996 BIOCHEMICAL M
Page 47 and 48: Vol. 224. No. 3, 1996 . BIOCHEMICAL
Page 49 and 50: ajochen. J. (1997)321. 211—216 (P
Page 51 and 52: Table 1 Effect al protejo kinase in
Page 53 and 54: ab cd — — — FIgure 4 Eblect o
Page 55 and 56: THE JOURNAL OP WOLOGICAL CI4EM¡SIR
Page 57 and 58: Immunop~rcipi¡añon of 32P-¡abeil
Page 59 and 60: permeabilizod hepatocytos and CPT-I
Page 61 and 62: (autbors’ urapublisbad rosullis).
Page 63 and 64: TItE JOURNAL OF BIoLoGICA[. CIIEMIS
Page 65 and 66: 2.3. Posible papel fisiológico del
Page 67 and 68: LOSS OF RESPONSE OF CARNITINE PALMI
Page 69 and 70: Lowenstein, Brandeis Uraiversity, W
Page 71: TABLE 2. Comparative effect of okad
Page 75 and 76: CONTROL OF FATTY ACID OXIDATION BY
Page 77 and 78: -co 100 n H o ocoo E ci, Method 50
Page 79 and 80: CONTROL OF FAflY ACID OXIDATION BY
Page 81 and 82: Vol. 233, No. 1. 1997 íonxc strera
Page 83 and 84: Vol. 233, No. 1, 1997 BIOCIjEMICAL
Page 85 and 86: Capítulo 2 DISCUSIÓN Relvultados
Page 87 and 88: Cavitulo .3 ¡3kcu~ión General y C
Page 89 and 90: Cacílulo 3 Esquema 2 >1. APOPTOSIS
Page 91: Canítulo 3 Discusión Géneral y C
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