.LDL receptor knock-out
mice are a physiological model particularly vulnerable to study the onset of
inflammation in non-alcoholic fatty liver disease.
BACKGROUND & AIMS:
Non-alcoholic steatohepatitis (NASH) involves steatosis combined with
inflammation, which can progress into fibrosis and cirrhosis.
Exploring the molecular mechanisms of NASH is highly dependent on the
availability of animal models.
Currently, the most commonly used animal models for NASH imitate
particularly late stages of human disease. Thus, there is a need for an animal
model that can be used for investigating the factors that potentiate the
inflammatory response within NASH.
We have previously shown that 7-day high-fat-high-cholesterol (HFC) feeding
induces steatosis and inflammation in both APOE2ki and Ldlr(-/-) mice.
However, it is not known whether the early inflammatory response observed
in these mice will sustain over time and lead to liver damage. We hypothesized
that the inflammatory response in both models is sufficient to induce liver
damage over time.
METHODS:
APOE2ki and Ldlr(-/-) mice were fed a chow or HFC diet for 3 months. C57Bl6/J
mice were used as control.
RESULTS:
Surprisingly, hepatic inflammation was abolished in APOE2ki mice, while it was
sustained in Ldlr(-/-) mice. In addition, increased apoptosis and hepatic
fibrosis was only demonstrated in Ldlr(-/-) mice. Finally,
bone-marrow-derived-macrophages of Ldlr(-/-) mice showed an increased
inflammatory response after oxidized LDL (oxLDL) loading compared to APOE2ki
mice.
CONCLUSION:
Ldlr(-/-) mice, but not APOE2ki mice, developed sustained hepatic inflammation
and liver damage upon long term HFC feeding due to increased sensitivity for
oxLDL uptake. Therefore, the Ldlr(-/-) mice are a promising physiological model
particularly vulnerable for investigating the onset of hepatic inflammation in
non-alcoholic steatohepatitis.
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Vragen aan dr. Ronit Shitri-Sverdlov:
"However, it is not known whether the early inflammatory response observed
in these mice will sustain over time and lead to liver damage."
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