Females are known to be more susceptible to alcoholic liver disease (ALD), but
the precise mechanism behind this increased susceptibility is not well understood. The
objective of this study was to identify the molecular mechanism behind the increased
susceptibility of females to alcoholic steatohepatitis (ASH). Female rats in ASH model
were found to have significantly higher neutrophilic infiltration in the liver as compared
to the males. Osteopontin (OPN), a member of the SIBLING family of proteins was also
found to be induced in females. Neutralizing OPN antibody experiments provided
further evidence that OPN acts as a chemokine in attracting neutrophils into the liver
making females more susceptible to ASH.
Since neutrophil transmigration in the liver is mediated by intergins, the
mechanism for OPN-mediated neutrophil infiltration was tested. Females in ASH had
significantly higher expression of α4β1 and α9β1 integrins, and animals treated with
neutralizing OPN antibody had significantly lower expression of these integrins, wherein hepatic neutrophilic infiltration was also decreased by 50% compared to the untreated
group. Immunoprecipitation experiments suggested the binding of OPN to α4β1 and α9β1
integrins. OPN-mediated neutrophilic infiltration was further confirmed using Boyden
chamber assays. Antibodies directed against α4, β1 integrins and SLAYGLR sequence
was also found to significantly inhibit neutrophilic migration in vitro, suggesting that
higher hepatic neutrophil chemokinesis in the female ASH appears to be mediated
through both α4β1 and α9β1 integrin signaling.
In addition, higher liver injury and higher expression of OPN in females were
also found to be regulated by estrogen in a biphasic pattern; ovariectomy resulted in
significantly increased liver injury compared to intact rats. Depending on dose, estradiol
supplementation in the ovariectomized rats fed ethanol resulted in both a protective and
damaging effect on liver.
Besides OPN, several other oxidative stress related proteins like Ferritin H
Chain, ER60, HSP60, Peroxiredoxin 6 were identified by proteomics approach. Females
in ASH were found to have differentially regulated levels of these proteins as compared
to their male counterparts, highlighting the potential novel mechanisms associated with
higher liver injury noted in our female rat ASH model.
|15 May 2009
|Ramaiah, Shashi K.
|Texas A and M University
|Book, Thesis, Electronic Dissertation, text
|electronic, application/pdf, born digital
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