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Desórdenes hepáticos causados por una dieta alta en colesterol. De los cambios transcriptómicos al carcinoma hepatocelular

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Luis E Gomez-Quiroz at Metropolitan Autonomous University
Luis E Gomez-Quiroz
Ismerai Pedraza
Ismerai Pedraza
Ismerai Pedraza
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Arturo Simoni-Nieves at Weizmann Institute of Science
Arturo Simoni-Nieves
Soraya Salas Silva at Hanyang University
Soraya Salas Silva
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XII CONGRESO NACIONAL
HEPATOLOGIA
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237
C
APÍTULO
Desórdenes hepáticos causados
por una dieta alta en colesterol.
De los cambios transcriptómicos
al carcinoma hepatocelular
I. Pedraza, A. Simoni Nieves, E.S. Salas Silva, J. González Ruiz, D.F. Calvisi, J.U. Marquardt,
D. Kershenobich Stalnikowicz, M.C. Gutiérrez Ruiz y L.E. Gómez Quiroz
INTRODUCCIÓN
Las dislipemias representan un desorden metabólico común
en todo el mundo, particularmente en los países latinoamerica-
nos
1
, lo cual condiciona múltiples enfermedades que van desde
las cardiovasculares, el síndrome metabólico, obesidad y las en-
fermedades hepáticas. En México se ha documentado muy bien
la susceptibilidad de varias dislipemias
2,3
, entre las cuales la hiper-
colesterolemia representa una de las principales y más frecuen-
tes
1
. El conocimiento y la caracterización de los subtipos de disli-
pemias deben contribuir a un mejor diagnóstico de las
hepatopatías relacionadas con ellas, de tal forma que pueda de-
rivar en mejores esquemas para ofrecer un pronóstico más acer-
tado y tratamientos optimizados.
TRIGLICÉRIDOS VERSUS COLESTEROL
Tenemos evidencia de que más que la cantidad de lípidos
depositados en el hígado, es la calidad o el tipo de lípidos lo que
marca el compromiso hepático, siendo el alto contenido de coles-
terol lo que representa el mayor daño hepatocelular no sólo en
animales de experimentación
4
, sino que también se ha caracteri-
zado muy bien en humanos
5
. Si bien cualquier tipo de dislipemia
debe ser causa de atención e intervención, las hipercolesterole-
mias recobran particular relevancia y requieren de una interven-
ción más cuidadosa y oportuna. Más allá de los ya bien conocidos
efectos cardiovasculares, la sobrecarga de colesterol en el hígado
induce un compromiso celular que puede derivar, en una primera
instancia, a la sensibilización ante una segunda agresión, o, en la
cronicidad, a la resistencia a la muerte que eventualmente puede
derivar en la transformación celular, lo cual no se ha observado
en la sobrecarga de triglicéridos.
En nuestra experiencia, la sobrecarga de colesterol induce un
problema serio de colestasis, que sensibiliza al hígado a una se-
gunda agresión que no puede compensar, por ejemplo, animales
alimentados con una dieta hipercolesterolémica (HC) (2% de co-
lesterol y 0.5% de colato de sodio). La dieta HC también induce
una sobrecarga muy elevada de triglicéridos, teniendo una pre-
sentación histológica característica con presencia de esteatosis
microvesicular. El incremento de triglicéridos puede representar
un efecto de protección, ya que son requeridos para empaquetar
al colesterol y sacarlo del hígado en VLDL. Una inspección más
detallada por microscopia electrónica de transmisión reveló
claros desórdenes mitocondriales y en el retículo endoplásmico
rugoso, así como una gran concentración de depósito de lípidos,
en relación con el tejido de ratones alimentados con una dieta
estándar.
Los ratones bajo una dieta HC fueron más susceptibles al
daño por colestasis obstructiva, lo cual indujo una muerte prema-
tura en estos animales (cinco días) en comparación con los con-
troles, que recibieron una dieta estándar, los cuales permanecie-
ron vivos más de un mes
6
.
Por otro lado, también hemos reportado que la dieta HC in-
duce un efecto más tóxico del acetaldehído, principal metabolito
en la biotransformación del etanol
7
.
La búsqueda de los mecanismos que condicionan el daño en
la sobrecarga de colesterol hepático ha llevado también a buscar
posibles mecanismos de protección.
Entre los principales efectos tóxicos encontrados está la gran
generación de especies reactivas de oxígeno, mediadas en gran
parte por un decremento en el glutatión, principal antioxidante
celular, particularmente a nivel mitocondrial
4
. El factor de creci-
miento de hepatocitos (HGF) representa una de las principales
contrapartes en el daño por colesterol. Previamente se había re-
portado que el HGF es un regulador maestro del estado redox
celular por un mecanismo que involucra a la NADPH oxidasa
8-10
.
El HGF es capaz de disminuir notablemente el estrés oxidante
generado por el colesterol, restableciendo casi por completo la
homeostasis celular, lo cual lo puede ubicar como un punto im-
portante de intervención terapéutica
11
.
CAMBIOS TRANSCRIPTÓMICOS
GENERADOS POR LA SOBRECARGA
DE COLESTEROL HEPÁTICO
El estudio transcriptómico global realizado en tejido hepático
de ratones alimentados por 30 días con una dieta HC reveló un
cambio en la expresión de 938 genes, de los cuales 439 se sobrex-
presaron y 499 se reprimieron de manera significativa (p 0.01)
con respecto al hígado de ratones alimentados con una dieta
estándar. El análisis de los resultados con software especializado
(Ingenuity Pathway Analysis, Ingenuity Systems, Inc.) reveló que
las principales redes moleculares afectas fueron el tráfico de pro-
teínas, ciclo celular, muerte celular y metabolismo lipídico, entre
otras, mientras que las posibles enfermedades comprometidas
238
XII Congreso Nacional de Hepatología
con la sobrecarga de colesterol fueron la enfermedad sistémica
hepática, las hematológicas y desórdenes endocrinos. Asimismo,
el análisis reveló el compromiso en el metabolismo lipídico (como
era de esperar), de vitaminas, biotransformación de xenobióticos,
y transporte molecular. Entre los genes con mayor sobrexpresión
se encuentran Gsta5, cd63, ccnd1, Hsd17b6, Ostbeta y Fhit, mien-
tras que los que mostraron mayor represión fueron Susd4, Hsd3b3,
Fdps, Cela1, Olig1 y Cyp2c19, entre otros. El compromiso en la bio-
síntesis de colesterol encontrado era igualmente esperado, ya que
se sabe que el colesterol dietético es un inhibidor de la síntesis de
novo de este lípido. El estrés oxidante, la respuesta de fase aguda
y el procesamiento de xenobióticos se encontraron igualmente
comprometidos en el hígado con una sobrecarga de colesterol.
En 2007 nuestro grupo reportó que el HGF y su receptor
c-Met inducen una regulación lipídica, aspecto que se desconocía
hasta ese momento
12
. El análisis transcriptómico reveló que el
factor de crecimiento regula varias de las enzimas, incluyendo a
Fasn, Acox1 y Scp2, entre otras. Los ratones deficientes en la se-
ñalización de c-Met (MetKO) sometidos a una dieta HC mostraron
un agravamiento en el depósito de lípidos hepático, estrés oxi-
dante y un incremento en proteínas antiapoptóticas como Mcl-1,
lo cual sugiere una paradoja interesante, ya que se observa lipo-
toxicidad, pero al mismo tiempo resistencia a la muerte
13
. Los
resultados reportados sugieren fuertemente que HGF/c-Met re-
presentan un regulador importante en la homeostasis del coles-
terol, por lo que la deficiencia en su señalización puede condicio-
nar presentaciones más agresivas de esteatosis, esteatohepatitis
y/o colestasis. Ahora sabemos que HGF/c-Met regulan la homeos-
tasis redox en las células hepáticas y que esto puede condicionar
a diversos desórdenes en el órgano
8
.
SOBRECARGA HEPÁTICA
DE COLESTEROL Y CÁNCER
Los datos transcriptómicos obtenidos tanto en ratones silves-
tres como MetKO alimentados o no con dieta HC revelaron, entre
otras cosas, un incremento en especies reactivas y al mismo tiem-
po una resistencia a la muerte, lo cual podría estar condicionando
un proceso de transformación celular, sobre todo si existe un es-
tímulo que tienda a dañar el ADN. Los datos obtenidos en nuestro
grupo de investigación han mostrado que la sobrecarga de coles-
terol hepático ejerce funciones promotoras de tumores. Los tu-
mores en ratones alimentados con una dieta HC mostraron ser
mucho más agresivos, siendo de mayor tamaño, mayor número
de lesiones, hipervascularizados y con metástasis en pulmón (da-
tos sometidos para publicación), no dejando duda de los posibles
efectos de una hipercolesterolemia crónica en asociación con
otros factores de riesgo para el desarrollo de cáncer.
La información obtenida prende focos rojos con respecto
a una vigilancia de las dislipemias y el posible incremento
de HCC.
CONCLUSIÓN
Los resultados de nuestro grupo de investigación y los repor-
tados en la literatura dejan claro que, entre las dislipemias, la hi-
percolesterolemia sensibiliza más al hígado ante el daño y condu-
ce cambios transcripcionales importantes que pueden conducir a
procesos de transformación celular y cáncer hepatocelular. Pode-
mos afirmar que la hipercolesterolemia puede conducir a la so-
brecarga de este lípido a nivel hepático, por lo que debe ser vigi-
lada estrechamente en los pacientes que puedan presentar
factores de riesgo o antecedentes heredofamiliares para el HCC.
La intervención oportuna en el control de la hipercolesterolemia
podría disminuir significativamente el riesgo en el desarrollo de
varias hepatopatías.
AGRADECIMIENTOS
El trabajo fue escrito con la ayuda y como producto de los
proyectos financiados por el CONACYT, Fronteras de la Ciencia
1320, CB-252942, así como por la Universidad Autónoma Metro-
politana Iztapalapa.
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Marí M, Caballero F, Colell A, et al Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis. Cell Metab. 2006;4(3):185-198
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  • Oct 2006
  • CELL METAB
The etiology of progression from steatosis to steatohepatitis (SH) remains unknown. Using nutritional and genetic models of hepatic steatosis, we show that free cholesterol (FC) loading, but not free fatty acids or triglycerides, sensitizes to TNF- and Fas-induced SH. FC distribution in endoplasmic reticulum (ER) and plasma membrane did not cause ER stress or alter TNF signaling. Rather, mitochondrial FC loading accounted for the hepatocellular sensitivity to TNF due to mitochondrial glutathione (mGSH) depletion. Selective mGSH depletion in primary hepatocytes recapitulated the susceptibility to TNF and Fas seen in FC-loaded hepatocytes; its repletion rescued FC-loaded livers from TNF-mediated SH. Moreover, hepatocytes from mice lacking NPC1, a late endosomal cholesterol trafficking protein, or from obese ob/ob mice, exhibited mitochondrial FC accumulation, mGSH depletion, and susceptibility to TNF. Thus, we propose a critical role for mitochondrial FC loading in precipitating SH, by sensitizing hepatocytes to TNF and Fas through mGSH depletion.
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