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TItE JOURNAL OF BIOLOGICAL CHEMISTRY (en rev¡oén) Ca 2 /CM-PKII aurapbospbarylation. AcLivated Ca2~/CM- PKII would pbospitarylate cytoskelotal camponents, perbaps cytokeratins 8 arad 18, tbereb>’ disrupting puliarive irahibitor>’ irateractiaras boliweara libe cytoskaiotora and CPT-I. StimulaLion of CPT-! upan disruptian of libo cytoskolaton would be also acbievod b>’ challenga of intact bepaLocyres lio IDPN or b>’ Lrealimenli of permeabilized bepaliocytes witb trypsla ira mild coradiliions. Stabilization of libo cyroskalaton wilib Laxol ma>’ provarat tite malorayi-CaA-indopendent aculio stimulaLian of CFI’-I. It is obvious ritat libe raotion tbat fatr’y acid traraslocation lato mitochondria ma>’ be controlad it>’ madulation of libe irateractioras botweera CFI’-I arad cyraskeletal componenlis (i.e. by a malara>’l-CoA-iradeporaderat mechanism) does raoli diminisb Lite imporlianca of maiorayl-CoA as a pitysiolagical madulator of CPT-I activir>’ (5,8). Ora ono barad, since libo pioneering work of McGarry arad coworkers (8,43), citarages la long-chaira fality acid oxidation urader man>’ diffarerat patbo-pbysiolagical situatioras bayo boen sbown La be liraked Lo changos ira iratracellular malonyl-CoA concentration and/or citaragos ira tite serasitivit>’ of CPT-I Lo ma]ora>’l-COA (1,2,5). On Lite aLbar batid, several observatioras suggesli libali malonyl-CoA-depondorat arad malarayl-CoA-iradeperaderat aculie control of bepatic CP’I’-I activir>’ migbt aperate in coracerli. First, Wc itave rocenLí>’ showra libat stimulatian of Lite AMP-activated proteira kinase -a majar protela kinasa ¡ravolved la libe control of bepatic lipid metabolism- laads to ara acrivation of bepatic CPT-I by ma]on>’l-CoA-dependont arad malon>’l-CoA-indapendent mocitanisms (44). Second, a fractiara of bapaLic acatyl-CoA carboxylase, tite arazyme resparasiblo for libe s>’rathosis of malon>’l-CoA, has beon reconlil>’ suggoslied Lo be bound ta Lbo cytaskoletan (45). Third, ir itas beon puÉ forward titar libe 280-KDa isoform of aceLyl-CaAcarbox>’lase migbL interact witb libe outer leafler of tbe mitocitoradrial autor membrana ira order Lo citannel malon>’l-CoA for CP’I’-I initibition (46). Fourtb, tite rocent obsorvation libar Lite bulk of tite CPT-I protein seems Lo face libo cytoplasmic sido of Lite mitocitandrial auter membrane (29) makes more Iikel>’ LitaL interactiaras beliwoon CFI’-I arad cytoskeleta] camparaerat; migbt occur. Ira tbo conten of tbe emergirag role of cytoskelolial filamentaus raoNrorks la intracelular sigraaling (47), currarat resoarcb ira our laboratorios is focussed ora Lito possible axisrenca of a coardinalie control of CPT-! arad acet>4-CoA carbax>’lase activities by modulation of interaction; between tite cylioskoletora and libe mitochoradrial autor membrarae. .4cknow/edgements - Wa are iradetited to Dr. Ismael Gaiya arad Ms. Teresa Gómez del Pulgar for expart techaical asistarace, as well as Lo Dr. Alejandra Alonso arad Dr. Jean Eraracois Leterrier for ha¡pfuL critical commerats. REFERENCES 1. Mcúarr>’, J.D., Woeltja, K.F., Kuwajinia, M., arad Foster, D.W. (1989) Diabetes Metab. Rey. 5, 271-284 2. Zammit, VA. (1994) Diabetes Rey. 2, 132-155 3. Guzmán, M., arad Gaelen, M.J.H. ’, M., Contasse, V., Lefebvre, H., Dalarue, C., arad Vaudwy, H. (1994) Am. 1. Physioi 266, E202-E210 19. Da Loof, A., Broeck, J., arad Jarassen, 1. (1996) Inc Rey. Cytol. 166, 1-58 20. Haagsmara, H.P., de Haas, C.G.M., van Golda, L.M.G., arad Gaelen, MJ.H. (1981) Biochim. Biophys. Acta 665, 1-7 21. Tokumitsi, H., Chijiwa, T., Hagiwara, M., Mizutaní, A., Taresawa, M., arad Hidaka, H. (1990)1 Rio! Chem. 265, 43154320 22. Fuchs, E., arad Wabar, K. (1994) Annu. Rey. Biochem. 63, 345-382 23. Toivola, DM., Goidmara, R.D., Garrod, D.R., arad Eriksson, J.E. (1997) J. Ccli Sci. 110, 23-33 24. Inagak>’, M., Inagaki, 14., Takahashi, T., arad Takay, Y. (1997) £ Biochem. (Tokyo) 121, 407414 25. Baraiter-Hahn, J., arad Vóth, M. (1994) Micmsc. Res. Tech. 27,, 198-219 26. Letarrier, J.F., Rusakov, DA., Nelson, B.D., arad Lindéra, M. (1994) Microsc. Res. Tech. 27, 233-261 27. Fontaine, EM., Keriet, C., Laratuajoul, 5., Rigouiet, M., Leverve, X.M., and Saks, VA. (1995) Biochem. Riophys. Res. Comman. 213, 138-146 28. Kashfi, K., and Cook, GA. (1992) Biochem. £ 282, 909- 914. 29. Fraser, E., Costorphina, CG., arad Zarairaiit, VA. (1997) Biochem. J. 323, 711-718 30. Lundéra, M., arad Karlsson, 0. (1996) Bloc/acm. Biophys. Res. Commun. 218, 833-836 31. Stromer, M.H.. arad Bedayan, M. (1990) Cd Motí! Cytoskeleton 17, 11-18
TItE JOURNAL OF BIoLoGICA[. CIIEMISTRY (en re~Sión) 32. Almahbobi, O., Wiliams, Li., arad Hall, EF. (1992) Sip. CefI Res. 200, 361-369 33. Bernier-Valeratira, F., arad Rousset, B. (1982) J. Bid. ’, A., arad Capetanaki, Y. (1996)1. Ccii Bici. 134, 1255-1270 38. Omar>’, MB., arad Ku, NO. (1997) Hepaíology 25, 1043- 1048 39. Fiskum, M, Craig, S.W., Dador, G.L., and Lehninger, AL. (1980) ¡‘mc. NiaL Aco4. Sci. USA. 77, 3430-3434 40. Guzmán, M., Velasco, O., and Castro, J. (1996) Am. £ Physioi. 270, 0710-0707 41. Ko, 14.0., arad Omar>’, E. (1994)1. Ccli Bici 127. 161- 171 42. Cadrin, M., McFarlane-Anderson, N., Aasheim, L.H., Kawahara, H., Fraraks, Di., Marcaau, N., arad French, S.W. (1992) Ccli? Signal. 4, 715-722 43. McGarr>’, J.D., Mannaerrs, GP., arad Foster, D.W. (1977) ¿ Clin. Invest. 60, 265-270 44. Velasco, 0., Geelen, Mi.H., arad Guzmán, M. (1997) A,rh. Biochem. Biophys. 337, 169-175 45. Gealen, Mi.H., Bijieveld, C., Velasco, G., Waraders, RAJ., arad Guzmán, M. (1997) Bloc/acm. Biophys. Res. Commun. 233, 253-257. 46. Ha, 3., Lee, J.K., Kim, K.S., Witters, LA., arad Kim, K.H. (1996) ¡‘mc. Noii Acad. Sri. USA. 93, 11466- 11470. 47. Forgaes, G. (1995) ¿ Cefi Sci. 108, 2131-2143 9
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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
Page 13 and 14: 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: (autbors’ urapublisbad rosullis).
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 and 72: TABLE 2. Comparative effect of okad
Page 73 and 74: ARCHIVES OF BIOCHEMJSTRY AND BIOPHY
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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