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.
Development of hepatic fibrosis occurs normally in AMPK-deficient mice
Alain Da Silva Morais, Jorge Abarca-Quinones, Bruno Guigas, Benoit Viollet, Peter Stärkel, Yves Horsmans, Isabelle A. Leclercq; Development of hepatic fibrosis occurs normally in AMPK-deficient mice. Clin Sci (Lond) 1 March 2010; 118 (6): 411–420. doi: https://doi.org/10.1042/CS20090293
Download citation file: