Development of hepatic fibrosis occurs normally in AMPK-deficient mice.
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 AMPKalpha1 catalytic subunit (AMPKalpha1-/-) or their littermates (AMPKalpha1+/+). Liver fibrosis was induced in vivo in AMPKalpha1-/- and AMPKalpha1+/+ mice by repeated injections of CCl(4) (carbon tetrachloride). During culture activation of HSCs, AMPK protein and activity significantly increased and regulatory AMPKgamma3 mRNA was specifically up-regulated. Stimulation of AMPK activity by AICAR inhibited HSC proliferation, as expected, as well as collagen alpha1(I) expression. Importantly, AMPKalpha1 deletion inhibited proliferation of HSCs, but not fibrogenesis, in vivo. Moreover, AMPKalpha1 deletion was not associated with enhanced CCl(4)-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 gamma3 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.
*Gastroenterology Laboratory, Université catholique de Louvain (UCL), B-1200 Brussels, Belgium.
Alain
A
da Silva Morais
Jorge
J
Abarca-Quinones
Bruno
B
Guigas
Benoit
B
Viollet
Peter
P
Stärkel
Yves
Y
Horsmans
Isabelle A
IA
Leclercq
D055372:AMP-Activated Protein Kinases / Q000172:deficiency*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D005260:Female; D055166:Hepatic Stellate Cells / Q000166:cytology; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000201:enzymology*; D051379:Mice; D012313:RNA / Q000378:metabolism; D012265:Ribonucleotides / Q000378:metabolism
D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D012313:RNA; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide