Development of hepatic fibrosis occurs normally in AMPK-deficient mice.

last updated: 2013-11-07
TitleDevelopment of hepatic fibrosis occurs normally in AMPK-deficient mice.
Publication TypePapers in Scientific Journals
Year of Publication2009
Authorsda Silva Morais A., Abarca-Quinones J., Guigas B., Viollet B., Stärkel P., Horsmans Y., and Leclercq I. A.

Inhibition or blockade of HSCs (hepatic stellate cells), the main matrix-producing cells involved in
the wound-healing response, represents an attractive strategy for the treatment of liver fibrosis.
In vitro studies have shown that activation of AMPK (AMP-activated protein kinase), a key player in
the regulation of cellular energy homoeostasis, inhibits proliferation of myofibroblasts derived
from HSCs. If AMPK is a true regulator of fibrogenesis then defective AMPK activity would
enhance fibrogenesis and hepatic fibrosis. To test this, in the present work, in vitro studies were
performed on mouse primary HSCs treated or not with the AMPK activator AICAR (5-amino-4-
imidazolecarboxamide ribonucleotide) or isolated from mice lacking the AMPKα1 catalytic subunit
(AMPKα1−/−) or their littermates (AMPKα1+/+). Liver fibrosis was induced in vivo in AMPKα1−/−
and AMPKα1+/+ mice by repeated injections of CCl4 (carbon tetrachloride). During culture
activation of HSCs, AMPK protein and activity significantly increased and regulatory AMPKγ3
mRNA was specifically up-regulated. Stimulation of AMPK activity by AICAR inhibited HSC
proliferation, as expected, as well as collagen α1(I) expression. Importantly, AMPKα1 deletion
inhibited proliferation of HSCs, but not fibrogenesis, in vivo. Moreover, AMPKα1 deletion was
not associated with enhanced CCl4-induced fibrosis in vivo. In conclusion, our present findings
demonstrate that HSC transdifferentiation is associated with increased AMPK activity that could
relate to the stabilization of AMPK complex by the γ3 subunits. Activation of AMPK in HSCs
inhibits in vitro fibrogenesis. By contrast, low AMPK activity does not prevent HSC activation
in vitro nor in in vivo fibrosis.

JournalClinical Science
Date Published2009-12-14
Keywords: 5-amino-4-imidazolecarboxamide ribonucleotide (AICAR), AMP-activated kinase (AMPK), Collagen, hepatic stellate cell, transdifferentiation, fibrosis
Peer reviewedno

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