| Popis: |
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 AMPK alpha 1 catalytic subunit (AMPK alpha 1(-/-)) or their littermates (AMPK alpha 1(+/+)). Liver fibrosis was induced in vivo in AMPK alpha 1(-/-) and AMPK alpha 1(+/+) mice by repeated injections of CCl4 (carbon tetrachloride). During culture activation of HSCs, AMPK protein and activity significantly increased and regulatory AMPK gamma 3 mRNA was specifically up-regulated. Stimulation of AMPK activity by AICAR inhibited HSC proliferation, as expected, as well as collagen alpha 1(1) expression. Importantly, AMPK alpha 1 deletion inhibited proliferation of HSCs, but not fibrogenesis, in vivo. Moreover, AMPK alpha 1 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 gamma 3 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. |
