Editorial

The future of fatty livers

Carmen Peralta, Joan Rosello-Catafau*

Department of Experimental Pathology, Instituto de Investigaciones Biomedicas de Barcelona-Consejo Superior de Investigaciones Cientıficas,

Institut d’Investigacions Biomediques August Pi i Sunyer, Rosello 161, 08036-Barcelona, Spain

See Article, pages 82–88

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 [1–7]. Thus, a considerable number of fatty donor

livers are now discarded, further accentuating the critical

shortage of human donor livers [4–7]. 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-a therapy, are clinically available in

normothermic conditions and no protective strategy is

clinically available for liver transplantation [8]. 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 [9,10].

One surgical strategy has been applied successfully by

Clavien [11,12] 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 [13,14].

Caraceni et al. [15], 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

[16,17]. The question is what goes wrong, and exactly how

does this happen?. Does steatosis affect oxidative phos-

phorylation during preservation, and if so, how?.

Caraceni et al. [15] 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 [18,19]. 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]. 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] 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].

If this happens in grafts that are, in principle, optimal for

transplantation, surgeons will be even less willing to

0168-8278/$30.00 q 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

doi:10.1016/j.jhep.2004.05.002

Journal of Hepatology 41 (2004) 149–151

www.elsevier.com/locate/jhep

* Corresponding author. Tel.: þ34-933638300; fax: þ34-933638301.

E-mail address: jrcbam@iibb.csic.es (J. Rosello-Catafau).

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 [21–23]. 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 [24–26]. In addition, mitochondrial membrane

permeability transition mediates mitochondrial pathway of

apoptosis in hepatocytes exposed to acute ethanol [27]. 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]. The mechan-

isms by which this drug protects mitochondria against the

deleterious effects of I/R involve inhibition of permeability

transition pore opening [29]. 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.

Acknowledgements

Supported by The Ministerio de Ciencia y Tecnologıa

(project grant no. BFI 2002-00704 and BFI 2003-00912 and

Ramon 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.

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