The future of fatty livers

Abstract

Among other factors, unhealthy lifestyles associated with the consumption of alcohol and inappropriate diets have increased the proportion of fatty livers. Hepatic steatosis is a major risk factor for liver surgery and transplantation, and fatty livers are unsuitable for many reasons. Operative mortality associated with steatosis exceeds 14%, compared with 2% for healthy livers, and the risks of primary nonfunction and dysfunction after surgery are similarly higher [1Huguet C. Gavelli A. Harb J. Roger-Clement R. De Millo D. Lasserre M. et al.L'ischemie du foie de plus d'une heure est-elle un facteur de gravité des hepatectomies? À propos de 19 cas.Chirurgie. 1991; 117: 351-356PubMed Google Scholar, 2Behrns K.E. Tsiotos G.G. DeSouza N.F. Krishna M.K. Ludwig J. Nagorney D.M. Hepatic steatosis as a potential risk factors for major hepatic resection.J Gastrointest Surg. 1998; 2: 292-298Crossref PubMed Scopus (337) Google Scholar, 3Selzner M. Clavien P.A. Resection of liver tumors: special emphasis on neoadjuvant and adjuvant therapy.in: Malden M.A. Malignant liver tumors-current and emerging therapies. Blackwell Science, Oxford1999: 137-149Google Scholar, 4Strasberg S.M. Howard T.K. Molmenti E.P. Hertl M. Selecting the donor liver: risk factors for poor function after orthotopic liver transplantation.Hepatology. 1994; 20: 829-838Crossref PubMed Scopus (479) Google Scholar, 5D'Alessandro A.M. Kalayoglu M. Sollinger H.W. Hoffmann R.M. Reed A. Knechtle S.J. et al.The predictive value of donor liver biopsies for the development of primary nonfunction after orthotopic liver transplantation.Transplant Proc. 1991; 23: 1536-1537PubMed Google Scholar, 6Todo S. Demetris A.J. Makowka I. Teperman I. Podesta L. Shaver T. et al.Primary nonfunction of hepatic allografts with preexisting fatty infiltration.Transplantation. 1989; 47: 903-905Crossref PubMed Scopus (317) Google Scholar, 7Trevisani F. Colantoni A. Caraceni P. Van Thiel D.H. The use of donor fatty liver for liver transplantation: a challenge or a quagmire?.J Hepatol. 1996; 22: 114-121Abstract Full Text PDF Scopus (81) Google Scholar]. Thus, a considerable number of fatty donor livers are now discarded, further accentuating the critical shortage of human donor livers [4Strasberg S.M. Howard T.K. Molmenti E.P. Hertl M. Selecting the donor liver: risk factors for poor function after orthotopic liver transplantation.Hepatology. 1994; 20: 829-838Crossref PubMed Scopus (479) Google Scholar, 5D'Alessandro A.M. Kalayoglu M. Sollinger H.W. Hoffmann R.M. Reed A. Knechtle S.J. et al.The predictive value of donor liver biopsies for the development of primary nonfunction after orthotopic liver transplantation.Transplant Proc. 1991; 23: 1536-1537PubMed Google Scholar, 6Todo S. Demetris A.J. Makowka I. Teperman I. Podesta L. Shaver T. et al.Primary nonfunction of hepatic allografts with preexisting fatty infiltration.Transplantation. 1989; 47: 903-905Crossref PubMed Scopus (317) Google Scholar, 7Trevisani F. Colantoni A. Caraceni P. Van Thiel D.H. The use of donor fatty liver for liver transplantation: a challenge or a quagmire?.J Hepatol. 1996; 22: 114-121Abstract Full Text PDF Scopus (81) Google Scholar]. In this context, an appropriate strategy to improve the viability of steatotic donor livers is urgently needed.In spite of intense research, currently only a few pharmacological protective strategies, consisting of anti-tumor necrosis factor-α therapy, are clinically available in normothermic conditions and no protective strategy is clinically available for liver transplantation [[8]Selzner M. Clavien P.A. Fatty liver in liver transplantation and surgery.Semin Liver Dis. 2001; 21: 105-113Crossref PubMed Scopus (373) Google Scholar]. In our opinion, the lack of protection is due to the multiple and different mechanisms of ischemia-reperfusion (I/R) injury between normal and steatotic livers, as well as between different types of steatosis [9Selzner M. Rüdiger H.A. Sindram D. Madden J. Clavien P.A. Mechanisms of ischemic injury are different in the steatotic and normal rat liver.Hepatology. 2000; 32: 1280-1288Crossref PubMed Scopus (234) Google Scholar, 10Serafı́n A. Roselló-Catafau J. Prats N. Xaus C. Gelpı́ E. Peralta C. Ischemic preconditioning increases the tolerance of fatty liver to hepatic ischemia-reperfusion injury in the rat.Am J Pathol. 2002; 161: 587-601Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar].One surgical strategy has been applied successfully by Clavien [11Clavien P.A. Yadav S. Sindram D. Bentley R.C. Protective effects of ischemic preconditioning for liver resection performed under inflow occlusion in humans.Ann Surg. 2000; 232: 155-162Crossref PubMed Scopus (427) Google Scholar, 12Clavien P.A. Selzner M. Rudiger H.A. Graft R. Kadry Z. Rousson V. et al.A prospective randomized study in 100 consecutive patients undergoing major liver resection with versus without ischemic preconditioning.Ann Surg. 2003; 238: 843-852Crossref PubMed Scopus (431) Google Scholar] in patients with steatotic livers undergoing major resection. This consists of ischemic preconditioning, which prepares hepatocytes to respond favourably to hepatic I/R injury. Preconditioning is easy to apply, inexpensive and does not require the use of drugs with potential side effects. One disadvantage of preconditioning is that it requires a period of preischemic manipulation for organ protection [13Lee H.T. Mechanisms of ischemic preconditioning and clinical implications for multiorgan ischemic-reperfusion injury.J Cardiothor Vasc An. 1999; 13: 78-91Abstract Full Text PDF PubMed Scopus (19) Google Scholar, 14Rüdiger H.A. Clavien P.A. A cytotoxic drug against reperfusion injury?.Hepatology. 2000; 31: 533-535Crossref PubMed Scopus (14) Google Scholar].Caraceni et al. [[15]Caraceni P. Bianchi C. Domenicali M. Pertosa A.M. Maiolini E. Castelli G.P. et al.Impairement of mitochondrial oxidative phosphorylation in rat fatty liver exposed to preservation-reperfusion injury.J Hepatol. 2004; 41: 82-88Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar], in this issue of the Journal, suggest that the identification of new strategies to prevent mitochondrial injury during cold ischemia, and thus guarantee full recovery of function after reperfusion, is an important goal. In fact, different studies in experimental models of cold ischemia indicate severe deterioration of mitochondrial functions in fatty livers during preservation [16Hayashi M. Tokunaga Y. Fujita T. Tanaka K. Yamaoka Y. Ozawa K. The effect of cold preservation on steatotic graft viability in rat liver transplantation.Transplantation. 1993; 56: 282-287Crossref PubMed Scopus (67) Google Scholar, 17Fukumory T. Ohkohchi S. Tsukamoto S. Satomi S. Why is fatty liver unsuitable for transplantation? Deterioration of mitochondrial ATP synthesis and sinusoidal structure during cold preservation of a liver with steatosis.Transplant Proc. 1997; 29: 412-415Abstract Full Text PDF PubMed Scopus (59) Google Scholar]. The question is what goes wrong, and exactly how does this happen?. Does steatosis affect oxidative phosphorylation during preservation, and if so, how?.Caraceni et al. [[15]Caraceni P. Bianchi C. Domenicali M. Pertosa A.M. Maiolini E. Castelli G.P. et al.Impairement of mitochondrial oxidative phosphorylation in rat fatty liver exposed to preservation-reperfusion injury.J Hepatol. 2004; 41: 82-88Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar] performed a detailed examination of the electron respiratory chain, which led them to identify the elements responsible for mitochondrial alterations in fatty livers with great accuracy. They report that in fatty liver alteration of the oxidative phosphorylation activity during preservation is greatly enhanced by fatty infiltration resulting from damage of respiratory chain complex I and F0F1–ATP synthase. Why is this a significant study? Mitochondria have emerged as central regulators of cell death in a variety of pathological conditions. Cell death can occur by either necrosis or apoptosis and the intracellular adenosine triphosphate (ATP) level appears to play a role as a putative apoptosis/necrosis switch: when ATP depletion is severe, necrosis ensues before the activation of the energy-requiring apoptotic pathway [18Green R.D. Reed J.C. Mitochondria and apoptosis.Science. 1998; 281: 1309-1312Crossref PubMed Google Scholar, 19Newmeyer D.D. Ferguson-Miller S. Mitochondria: releasing power for life and unleashing the mechanisms of death.Cell. 2003; 112: 481-490Abstract Full Text Full Text PDF PubMed Scopus (1068) Google Scholar]. Thus, the relative susceptibility to apoptosis or necrosis during I/R is influenced by the ratio of glycolytic to respiratory ATP generation, which is also differentially affected by the disruption of mitochondrial function. Based on the above observations, it is not surprising that necrosis rather than apoptosis is the predominant process of cell death in fatty liver subjected to I/R [[9]Selzner M. Rüdiger H.A. Sindram D. Madden J. Clavien P.A. Mechanisms of ischemic injury are different in the steatotic and normal rat liver.Hepatology. 2000; 32: 1280-1288Crossref PubMed Scopus (234) Google Scholar]. Thus, understanding key aspects of mitochondrial dysfunction is a necessary step towards the elaboration of new protective strategies against I/R injury.On the other hand, although the study by Caraceni et al. [[15]Caraceni P. Bianchi C. Domenicali M. Pertosa A.M. Maiolini E. Castelli G.P. et al.Impairement of mitochondrial oxidative phosphorylation in rat fatty liver exposed to preservation-reperfusion injury.J Hepatol. 2004; 41: 82-88Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar] is interesting, there are also important considerations to be borne in mind. In human liver transplantation, a long ischemic period is a predictive factor for post-transplant graft dysfunction, and some transplantation groups hesitate to transplant liver grafts preserved for more than 10 h [[20]Klar E. Angelescu M. Zapletal C. Kraus T. Bredt M. Herfarth C. Definition of maximum cold ischemia time without reduction of graft quality in clinical liver transplantation.Transplant Proc. 1998; 30: 3683-3685Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar]. If this happens in grafts that are, in principle, optimal for transplantation, surgeons will be even less willing to transplant a steatotic liver after 18 h of ischemia. Moreover, discovering pharmacological strategies targeted to such specific components of the mitochondria as Complex I and F0F1–ATP synthase, which are found to be altered in fatty livers, is no easy task.Where do we go from here?. Experimental studies have shown that oxidative stress is constantly associated with fat accumulation, leading to a series of biochemical and ultrastructural mitochondrial abnormalities [21Vendemiale G. Grattagliano I. Caraceni P. Caraccio G. Dominicali M. DallÁgata M. et al.Mitochondrial oxidative injury metabolism alteration in rat fatty liver: effect of the nutritional status.Hepatology. 2001; 33: 808-815Crossref PubMed Scopus (138) Google Scholar, 22Cadwell S.H. Swerdlow R.H. Khan E.M. Iezzoni J.C. Hespenheide E.E. Parks J.K. et al.Mitochondrial abnormalities in non-alcoholic steatohepatitis.J Hepatol. 1999; 31: 430-434Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar, 23Lieber C.S. Biochemical and molecular basis of alcoholic-induced injury to liver and other tissues.N Engl J Med. 1998; 319: 1639-1650Google Scholar]. Thus, perhaps we could improve pharmacological modulation by examining the mechanisms responsible for mitochondrial alterations in steatotic livers. It is important to note that mitochondrial damage occurs mostly during cold ischemia in fatty liver. Thus, in our opinion, protective strategies should be applied before the steatotic graft is inserted into the recipient. In organ transplantation, apoptosis is shown to occur through the mitochondrial pathway and involves cold-induced mitochondrial permeability transition pore opening and, consequently, mitochondrial swelling, mitochondrial membrane rupture, and cytochrome translocation to the cytosol [24Salahudeen A.K. Joshi M. Jenkins J.K. Apoptosis versus necrosis during cold storage and rewarming of human renal proximal tubular cells.Transplantation. 2001; 72: 798-804Crossref PubMed Scopus (83) Google Scholar, 25Burns A.T. Davies D.R. McLaren A.J. Cerundolo L. Morris P.J. Fuggle S.V. Apoptosis in ischemia/reperfusion injury of human renal allografts.Transplantation. 1998; 66: 872-876Crossref PubMed Scopus (134) Google Scholar, 26Shalahudeen A.K. Huang H. Joshi M. Jenkins J.K. Targeting mitochondria to prevent cold storage-induced renal tubular cell injury.J Am Soc Nephrol. 2001; 12: 179AGoogle Scholar]. In addition, mitochondrial membrane permeability transition mediates mitochondrial pathway of apoptosis in hepatocytes exposed to acute ethanol [[27]Higuchi H. Adachi M. Miura S. Gores G.J. Ishii H. The mitochondrial permeability transition contributes to acute ethanol-induced apoptosis in rat hepatocytes.Hepatology. 2001; 34: 320-328Crossref PubMed Scopus (119) Google Scholar]. Here we should emphasize that recent studies in kidney indicate that a pharmacological substance, such as trimetazidine, added to preservation solutions has beneficial effects on the alterations in mitochondrial functions [[28]Faure J.P. Petit I. Zhang K. Dutheil D. Doucet C. Favreau F. et al.Protective roles of polyethylene glycol and trimetazidine against cold ischemia and reperfusion injuries of pig kidney grafts.Am J Transplant. 2004; 4: 495-504Crossref PubMed Scopus (41) Google Scholar]. The mechanisms by which this drug protects mitochondria against the deleterious effects of I/R involve inhibition of permeability transition pore opening [[29]Elimadi A. Jullien V. Tillemen J.P. Morin D. S-15176 inhibits mitochondrial permeability transition via a mechanism independent of its antioxidant properties.Eur J Pharmacol. 2003; 468: 93-101Crossref PubMed Scopus (26) Google Scholar]. Thus, might it be possible to extrapolate the results to hepatic I/R in order to increase the viability of steatotic livers?. The hope of finding new surgical and pharmacological therapeutic applications provides a strong impetus to identify the mechanisms responsible for the failure of fatty livers. We must continue with research in an attempt to improve the future of fatty livers. Of course, it would be no bad thing if we all looked after our liver, by adopting sensible dietary habits and life styles. Among other factors, unhealthy lifestyles associated with the consumption of alcohol and inappropriate diets have increased the proportion of fatty livers. Hepatic steatosis is a major risk factor for liver surgery and transplantation, and fatty livers are unsuitable for many reasons. Operative mortality associated with steatosis exceeds 14%, compared with 2% for healthy livers, and the risks of primary nonfunction and dysfunction after surgery are similarly higher [1Huguet C. Gavelli A. Harb J. Roger-Clement R. De Millo D. Lasserre M. et al.L'ischemie du foie de plus d'une heure est-elle un facteur de gravité des hepatectomies? À propos de 19 cas.Chirurgie. 1991; 117: 351-356PubMed Google Scholar, 2Behrns K.E. Tsiotos G.G. DeSouza N.F. Krishna M.K. Ludwig J. Nagorney D.M. Hepatic steatosis as a potential risk factors for major hepatic resection.J Gastrointest Surg. 1998; 2: 292-298Crossref PubMed Scopus (337) Google Scholar, 3Selzner M. Clavien P.A. Resection of liver tumors: special emphasis on neoadjuvant and adjuvant therapy.in: Malden M.A. Malignant liver tumors-current and emerging therapies. Blackwell Science, Oxford1999: 137-149Google Scholar, 4Strasberg S.M. Howard T.K. Molmenti E.P. Hertl M. Selecting the donor liver: risk factors for poor function after orthotopic liver transplantation.Hepatology. 1994; 20: 829-838Crossref PubMed Scopus (479) Google Scholar, 5D'Alessandro A.M. Kalayoglu M. Sollinger H.W. Hoffmann R.M. Reed A. Knechtle S.J. et al.The predictive value of donor liver biopsies for the development of primary nonfunction after orthotopic liver transplantation.Transplant Proc. 1991; 23: 1536-1537PubMed Google Scholar, 6Todo S. Demetris A.J. Makowka I. Teperman I. Podesta L. Shaver T. et al.Primary nonfunction of hepatic allografts with preexisting fatty infiltration.Transplantation. 1989; 47: 903-905Crossref PubMed Scopus (317) Google Scholar, 7Trevisani F. Colantoni A. Caraceni P. Van Thiel D.H. The use of donor fatty liver for liver transplantation: a challenge or a quagmire?.J Hepatol. 1996; 22: 114-121Abstract Full Text PDF Scopus (81) Google Scholar]. Thus, a considerable number of fatty donor livers are now discarded, further accentuating the critical shortage of human donor livers [4Strasberg S.M. Howard T.K. Molmenti E.P. Hertl M. Selecting the donor liver: risk factors for poor function after orthotopic liver transplantation.Hepatology. 1994; 20: 829-838Crossref PubMed Scopus (479) Google Scholar, 5D'Alessandro A.M. Kalayoglu M. Sollinger H.W. Hoffmann R.M. Reed A. Knechtle S.J. et al.The predictive value of donor liver biopsies for the development of primary nonfunction after orthotopic liver transplantation.Transplant Proc. 1991; 23: 1536-1537PubMed Google Scholar, 6Todo S. Demetris A.J. Makowka I. Teperman I. Podesta L. Shaver T. et al.Primary nonfunction of hepatic allografts with preexisting fatty infiltration.Transplantation. 1989; 47: 903-905Crossref PubMed Scopus (317) Google Scholar, 7Trevisani F. Colantoni A. Caraceni P. Van Thiel D.H. The use of donor fatty liver for liver transplantation: a challenge or a quagmire?.J Hepatol. 1996; 22: 114-121Abstract Full Text PDF Scopus (81) Google Scholar]. In this context, an appropriate strategy to improve the viability of steatotic donor livers is urgently needed. In spite of intense research, currently only a few pharmacological protective strategies, consisting of anti-tumor necrosis factor-α therapy, are clinically available in normothermic conditions and no protective strategy is clinically available for liver transplantation [[8]Selzner M. Clavien P.A. Fatty liver in liver transplantation and surgery.Semin Liver Dis. 2001; 21: 105-113Crossref PubMed Scopus (373) Google Scholar]. In our opinion, the lack of protection is due to the multiple and different mechanisms of ischemia-reperfusion (I/R) injury between normal and steatotic livers, as well as between different types of steatosis [9Selzner M. Rüdiger H.A. Sindram D. Madden J. Clavien P.A. Mechanisms of ischemic injury are different in the steatotic and normal rat liver.Hepatology. 2000; 32: 1280-1288Crossref PubMed Scopus (234) Google Scholar, 10Serafı́n A. Roselló-Catafau J. Prats N. Xaus C. Gelpı́ E. Peralta C. Ischemic preconditioning increases the tolerance of fatty liver to hepatic ischemia-reperfusion injury in the rat.Am J Pathol. 2002; 161: 587-601Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar]. One surgical strategy has been applied successfully by Clavien [11Clavien P.A. Yadav S. Sindram D. Bentley R.C. Protective effects of ischemic preconditioning for liver resection performed under inflow occlusion in humans.Ann Surg. 2000; 232: 155-162Crossref PubMed Scopus (427) Google Scholar, 12Clavien P.A. Selzner M. Rudiger H.A. Graft R. Kadry Z. Rousson V. et al.A prospective randomized study in 100 consecutive patients undergoing major liver resection with versus without ischemic preconditioning.Ann Surg. 2003; 238: 843-852Crossref PubMed Scopus (431) Google Scholar] in patients with steatotic livers undergoing major resection. This consists of ischemic preconditioning, which prepares hepatocytes to respond favourably to hepatic I/R injury. Preconditioning is easy to apply, inexpensive and does not require the use of drugs with potential side effects. One disadvantage of preconditioning is that it requires a period of preischemic manipulation for organ protection [13Lee H.T. Mechanisms of ischemic preconditioning and clinical implications for multiorgan ischemic-reperfusion injury.J Cardiothor Vasc An. 1999; 13: 78-91Abstract Full Text PDF PubMed Scopus (19) Google Scholar, 14Rüdiger H.A. Clavien P.A. A cytotoxic drug against reperfusion injury?.Hepatology. 2000; 31: 533-535Crossref PubMed Scopus (14) Google Scholar]. Caraceni et al. [[15]Caraceni P. Bianchi C. Domenicali M. Pertosa A.M. Maiolini E. Castelli G.P. et al.Impairement of mitochondrial oxidative phosphorylation in rat fatty liver exposed to preservation-reperfusion injury.J Hepatol. 2004; 41: 82-88Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar], in this issue of the Journal, suggest that the identification of new strategies to prevent mitochondrial injury during cold ischemia, and thus guarantee full recovery of function after reperfusion, is an important goal. In fact, different studies in experimental models of cold ischemia indicate severe deterioration of mitochondrial functions in fatty livers during preservation [16Hayashi M. Tokunaga Y. Fujita T. Tanaka K. Yamaoka Y. Ozawa K. The effect of cold preservation on steatotic graft viability in rat liver transplantation.Transplantation. 1993; 56: 282-287Crossref PubMed Scopus (67) Google Scholar, 17Fukumory T. Ohkohchi S. Tsukamoto S. Satomi S. Why is fatty liver unsuitable for transplantation? Deterioration of mitochondrial ATP synthesis and sinusoidal structure during cold preservation of a liver with steatosis.Transplant Proc. 1997; 29: 412-415Abstract Full Text PDF PubMed Scopus (59) Google Scholar]. The question is what goes wrong, and exactly how does this happen?. Does steatosis affect oxidative phosphorylation during preservation, and if so, how?. Caraceni et al. [[15]Caraceni P. Bianchi C. Domenicali M. Pertosa A.M. Maiolini E. Castelli G.P. et al.Impairement of mitochondrial oxidative phosphorylation in rat fatty liver exposed to preservation-reperfusion injury.J Hepatol. 2004; 41: 82-88Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar] performed a detailed examination of the electron respiratory chain, which led them to identify the elements responsible for mitochondrial alterations in fatty livers with great accuracy. They report that in fatty liver alteration of the oxidative phosphorylation activity during preservation is greatly enhanced by fatty infiltration resulting from damage of respiratory chain complex I and F0F1–ATP synthase. Why is this a significant study? Mitochondria have emerged as central regulators of cell death in a variety of pathological conditions. Cell death can occur by either necrosis or apoptosis and the intracellular adenosine triphosphate (ATP) level appears to play a role as a putative apoptosis/necrosis switch: when ATP depletion is severe, necrosis ensues before the activation of the energy-requiring apoptotic pathway [18Green R.D. Reed J.C. Mitochondria and apoptosis.Science. 1998; 281: 1309-1312Crossref PubMed Google Scholar, 19Newmeyer D.D. Ferguson-Miller S. Mitochondria: releasing power for life and unleashing the mechanisms of death.Cell. 2003; 112: 481-490Abstract Full Text Full Text PDF PubMed Scopus (1068) Google Scholar]. Thus, the relative susceptibility to apoptosis or necrosis during I/R is influenced by the ratio of glycolytic to respiratory ATP generation, which is also differentially affected by the disruption of mitochondrial function. Based on the above observations, it is not surprising that necrosis rather than apoptosis is the predominant process of cell death in fatty liver subjected to I/R [[9]Selzner M. Rüdiger H.A. Sindram D. Madden J. Clavien P.A. Mechanisms of ischemic injury are different in the steatotic and normal rat liver.Hepatology. 2000; 32: 1280-1288Crossref PubMed Scopus (234) Google Scholar]. Thus, understanding key aspects of mitochondrial dysfunction is a necessary step towards the elaboration of new protective strategies against I/R injury. On the other hand, although the study by Caraceni et al. [[15]Caraceni P. Bianchi C. Domenicali M. Pertosa A.M. Maiolini E. Castelli G.P. et al.Impairement of mitochondrial oxidative phosphorylation in rat fatty liver exposed to preservation-reperfusion injury.J Hepatol. 2004; 41: 82-88Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar] is interesting, there are also important considerations to be borne in mind. In human liver transplantation, a long ischemic period is a predictive factor for post-transplant graft dysfunction, and some transplantation groups hesitate to transplant liver grafts preserved for more than 10 h [[20]Klar E. Angelescu M. Zapletal C. Kraus T. Bredt M. Herfarth C. Definition of maximum cold ischemia time without reduction of graft quality in clinical liver transplantation.Transplant Proc. 1998; 30: 3683-3685Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar]. If this happens in grafts that are, in principle, optimal for transplantation, surgeons will be even less willing to transplant a steatotic liver after 18 h of ischemia. Moreover, discovering pharmacological strategies targeted to such specific components of the mitochondria as Complex I and F0F1–ATP synthase, which are found to be altered in fatty livers, is no easy task. Where do we go from here?. Experimental studies have shown that oxidative stress is constantly associated with fat accumulation, leading to a series of biochemical and ultrastructural mitochondrial abnormalities [21Vendemiale G. Grattagliano I. Caraceni P. Caraccio G. Dominicali M. DallÁgata M. et al.Mitochondrial oxidative injury metabolism alteration in rat fatty liver: effect of the nutritional status.Hepatology. 2001; 33: 808-815Crossref PubMed Scopus (138) Google Scholar, 22Cadwell S.H. Swerdlow R.H. Khan E.M. Iezzoni J.C. Hespenheide E.E. Parks J.K. et al.Mitochondrial abnormalities in non-alcoholic steatohepatitis.J Hepatol. 1999; 31: 430-434Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar, 23Lieber C.S. Biochemical and molecular basis of alcoholic-induced injury to liver and other tissues.N Engl J Med. 1998; 319: 1639-1650Google Scholar]. Thus, perhaps we could improve pharmacological modulation by examining the mechanisms responsible for mitochondrial alterations in steatotic livers. It is important to note that mitochondrial damage occurs mostly during cold ischemia in fatty liver. Thus, in our opinion, protective strategies should be applied before the steatotic graft is inserted into the recipient. In organ transplantation, apoptosis is shown to occur through the mitochondrial pathway and involves cold-induced mitochondrial permeability transition pore opening and, consequently, mitochondrial swelling, mitochondrial membrane rupture, and cytochrome translocation to the cytosol [24Salahudeen A.K. Joshi M. Jenkins J.K. Apoptosis versus necrosis during cold storage and rewarming of human renal proximal tubular cells.Transplantation. 2001; 72: 798-804Crossref PubMed Scopus (83) Google Scholar, 25Burns A.T. Davies D.R. McLaren A.J. Cerundolo L. Morris P.J. Fuggle S.V. Apoptosis in ischemia/reperfusion injury of human renal allografts.Transplantation. 1998; 66: 872-876Crossref PubMed Scopus (134) Google Scholar, 26Shalahudeen A.K. Huang H. Joshi M. Jenkins J.K. Targeting mitochondria to prevent cold storage-induced renal tubular cell injury.J Am Soc Nephrol. 2001; 12: 179AGoogle Scholar]. In addition, mitochondrial membrane permeability transition mediates mitochondrial pathway of apoptosis in hepatocytes exposed to acute ethanol [[27]Higuchi H. Adachi M. Miura S. Gores G.J. Ishii H. The mitochondrial permeability transition contributes to acute ethanol-induced apoptosis in rat hepatocytes.Hepatology. 2001; 34: 320-328Crossref PubMed Scopus (119) Google Scholar]. Here we should emphasize that recent studies in kidney indicate that a pharmacological substance, such as trimetazidine, added to preservation solutions has beneficial effects on the alterations in mitochondrial functions [[28]Faure J.P. Petit I. Zhang K. Dutheil D. Doucet C. Favreau F. et al.Protective roles of polyethylene glycol and trimetazidine against cold ischemia and reperfusion injuries of pig kidney grafts.Am J Transplant. 2004; 4: 495-504Crossref PubMed Scopus (41) Google Scholar]. The mechanisms by which this drug protects mitochondria against the deleterious effects of I/R involve inhibition of permeability transition pore opening [[29]Elimadi A. Jullien V. Tillemen J.P. Morin D. S-15176 inhibits mitochondrial permeability transition via a mechanism independent of its antioxidant properties.Eur J Pharmacol. 2003; 468: 93-101Crossref PubMed Scopus (26) Google Scholar]. Thus, might it be possible to extrapolate the results to hepatic I/R in order to increase the viability of steatotic livers?. The hope of finding new surgical and pharmacological therapeutic applications provides a strong impetus to identify the mechanisms responsible for the failure of fatty livers. We must continue with research in an attempt to improve the future of fatty livers. Of course, it would be no bad thing if we all looked after our liver, by adopting sensible dietary habits and life styles. Supported by The Ministerio de Ciencia y Tecnologı́a (project grant no. BFI 2002-00704 and BFI 2003-00912 and Ramón y Cajal research contract to Carmen Peralta), Madrid, Spain. We thank Robin Rycroft at the Language Advisory Service at the University of Barcelona for revising the English text.