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Development of hepatic fibrosis occurs normally in AMPK-deficient mice

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Da Silva Morais, Alain [UCL] Abarca-Quinones, Jorge [UCL] Guigas, Bruno [UCL] Viollet, Benoit Starkel, Peter [UCL] Horsmans, Yves [UCL] Leclercq, Isabelle [UCL]

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.

Document type Article de périodique (Journal article) – Article de recherche – Journal Article, Research Support, Non-U.S. Gov't
Access type Accès restreint
Publication date 2010
Language Anglais
Journal information "Clinical Science" - Vol. 118, no. 6, p. 411-420 (2010)
Peer reviewed yes
Publisher Portland Press Ltd. ((United Kingdom) London)
issn 0143-5221
e-issn 1470-8736
Publication status Publié
Affiliations UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie
UCL - SSS/DDUV - Institut de Duve
UCL - (SLuc) Service d'hépato-gastro-entérologie
MESH Subject Ribonucleotides - metabolism ; RNA - metabolism ; Mice ; Liver Cirrhosis - enzymology ; Immunohistochemistry ; Hepatic Stellate Cells - cytology ; Female ; Cells, Cultured ; Cell Transdifferentiation ; Animals ; Aminoimidazole Carboxamide - analogs & derivatives - metabolism ; AMP-Activated Protein Kinases - deficiency
Links
  1. Kamada Yoshihiro, Tamura Shinji, Kiso Shinichi, Matsumoto Hitoshi, Saji Yukiko, Yoshida Yuichi, Fukui Koji, Maeda Norikazu, Nishizawa Hitoshi, Nagaretani Hiroyuki, Okamoto Yoshihisa, Kihara Shinji, Miyagawa Jun-ichiro, Shinomura Yasuhisa, Funahashi Tohru, Matsuzawa Yuji, Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin, 10.1053/j.gastro.2003.08.029
  2. Ding X, Am. J. Pathol., 166, 1655 (2005)
  3. Targher Giovanni, Bertolini Lorenzo, Rodella Stefano, Zoppini Giacomo, Scala Luca, Zenari Luciano, Falezza Giancarlo, Associations between plasma adiponectin concentrations and liver histology in patients with nonalcoholic fatty liver disease, 10.1111/j.1365-2265.2006.02527.x
  4. Yamauchi Toshimasa, Nio Yasunori, Maki Toshiyuki, Kobayashi Masaki, Takazawa Takeshi, Iwabu Masato, Okada-Iwabu Miki, Kawamoto Sachiko, Kubota Naoto, Kubota Tetsuya, Ito Yusuke, Kamon Junji, Tsuchida Atsushi, Kumagai Katsuyoshi, Kozono Hideki, Hada Yusuke, Ogata Hitomi, Tokuyama Kumpei, Tsunoda Masaki, Ide Tomohiro, Murakami Kouji, Awazawa Motoharu, Takamoto Iseki, Froguel Philippe, Hara Kazuo, Tobe Kazuyuki, Nagai Ryozo, Ueki Kohjiro, Kadowaki Takashi, Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions, 10.1038/nm1557
  5. Hardie D. Grahame, Minireview: The AMP-Activated Protein Kinase Cascade: The Key Sensor of Cellular Energy Status, 10.1210/en.2003-0982
  6. Kahn Barbara B., Alquier Thierry, Carling David, Hardie D. Grahame, AMP-activated protein kinase: Ancient energy gauge provides clues to modern understanding of metabolism, 10.1016/j.cmet.2004.12.003
  7. Carling David, AMP-activated protein kinase: balancing the scales, 10.1016/j.biochi.2004.10.017
  8. Igata M., Adenosine Monophosphate-Activated Protein Kinase Suppresses Vascular Smooth Muscle Cell Proliferation Through the Inhibition of Cell Cycle Progression, 10.1161/01.res.0000185823.73556.06
  9. Jones Russell G., Plas David R., Kubek Sara, Buzzai Monica, Mu James, Xu Yang, Birnbaum Morris J., Thompson Craig B., AMP-Activated Protein Kinase Induces a p53-Dependent Metabolic Checkpoint, 10.1016/j.molcel.2005.03.027
  10. Imamura Kazuhiro, Ogura Tsutomu, Kishimoto Atsuhiro, Kaminishi Michio, Esumi Hiroyasu, Cell Cycle Regulation via p53 Phosphorylation by a 5′-AMP Activated Protein Kinase Activator, 5-Aminoimidazole- 4-Carboxamide-1-β--Ribofuranoside, in a Human Hepatocellular Carcinoma Cell Line, 10.1006/bbrc.2001.5627
  11. Caligiuri Alessandra, Bertolani Cristiana, Guerra Cristina Tosti, Aleffi Sara, Galastri Sara, Trappoliere Marco, Vizzutti Francesco, Gelmini Stefania, Laffi Giacomo, Pinzani Massimo, Marra Fabio, Adenosine monophosphate-activated protein kinase modulates the activated phenotype of hepatic stellate cells, 10.1002/hep.21995
  12. Adachi Masayuki, Brenner David A., High molecular weight adiponectin inhibits proliferation of hepatic stellate cells via activation of adenosine monophosphate-activated protein kinase, 10.1002/hep.21991
  13. Jorgensen S, J. Biol. Chem., 279, 1070 (2004)
  14. Da Silva Morais A, Int. J. Mol. Med., 19, 105 (2007)
  15. Leclercq Isabelle A, Farrell Geoffrey C, Schriemer Rixt, Robertson Graham R, Leptin is essential for the hepatic fibrogenic response to chronic liver injury, 10.1016/s0168-8278(02)00102-2
  16. Livak Kenneth J., Schmittgen Thomas D., Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method, 10.1006/meth.2001.1262
  17. Da Silva Morais Alain, Lebrun Valérie, Abarca-Quinones Jorge, Brichard Sonia, Hue Louis, Guigas Bruno, Viollet Benoit, Leclercq Isabelle A., Prevention of steatohepatitis by pioglitazone: Implication of adiponectin-dependent inhibition of SREBP-1c and inflammation, 10.1016/j.jhep.2008.10.027
  18. Mitchelhill K, J. Biol. Chem., 269, 2361 (1994)
  19. Guigas B., Bertrand L., Taleux N., Foretz M., Wiernsperger N., Vertommen D., Andreelli F., Viollet B., Hue L., 5-Aminoimidazole-4-Carboxamide-1- -D-Ribofuranoside and Metformin Inhibit Hepatic Glucose Phosphorylation by an AMP-Activated Protein Kinase-Independent Effect on Glucokinase Translocation, 10.2337/diabetes.55.04.06.db05-1178
  20. Inoki Ken, Zhu Tianqing, Guan Kun-Liang, TSC2 Mediates Cellular Energy Response to Control Cell Growth and Survival, 10.1016/s0092-8674(03)00929-2
  21. Luo Zhijun, Saha Asish K., Xiang Xiaoqin, Ruderman Neil B., AMPK, the metabolic syndrome and cancer, 10.1016/j.tips.2004.12.011
  22. Friedman S. L., Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver, 10.1152/physrev.00013.2007
  23. Imamura Michio, Ogawa Tadashi, Sasaguri Yasuyuki, Chayama Kazuaki, Ueno Hikaru, Suppression of macrophage infiltration inhibits activation of hepatic stellate cells and liver fibrogenesis in rats, 10.1053/j.gastro.2004.10.005
  24. Knittel Thomas, Dinter Christina, Kobold Dominik, Neubauer Katrin, Mehde Mirko, Eichhorst Sören, Ramadori Giuliano, Expression and Regulation of Cell Adhesion Molecules by Hepatic Stellate Cells (HSC) of Rat Liver, 10.1016/s0002-9440(10)65262-5
  25. Mahlapuu M, Am. J. Physiol. Endocrinol. Metab., 286, E194 (2004)
  26. Sakamoto Kei, Hirshman Michael F., Aschenbach William G., Goodyear Laurie J., Contraction Regulation of Akt in Rat Skeletal Muscle, 10.1074/jbc.m112410200
  27. Martin K, Adv. Cancer Res., 86, 1 (2002)
  28. Gwinn Dana M., Shackelford David B., Egan Daniel F., Mihaylova Maria M., Mery Annabelle, Vasquez Debbie S., Turk Benjamin E., Shaw Reuben J., AMPK Phosphorylation of Raptor Mediates a Metabolic Checkpoint, 10.1016/j.molcel.2008.03.003
  29. Zhang Bei B., Zhou Gaochao, Li Cai, AMPK: An Emerging Drug Target for Diabetes and the Metabolic Syndrome, 10.1016/j.cmet.2009.03.012
  30. Nagata D., AMP-Activated Protein Kinase Inhibits Angiotensin II-Stimulated Vascular Smooth Muscle Cell Proliferation, 10.1161/01.cir.0000136025.96811.76
  31. Rattan Ramandeep, Giri Shailendra, Singh Avtar K., Singh Inderjit, 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside Inhibits Cancer Cell Proliferationin Vitroandin Vivovia AMP-activated Protein Kinase, 10.1074/jbc.m507443200
  32. Huang Xu, Wullschleger Stephan, Shpiro Natalia, McGuire Victoria A., Sakamoto Kei, Woods Yvonne L., Mcburnie Wendy, Fleming Stewart, Alessi Dario R., Important role of the LKB1–AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice, 10.1042/bj20080557
  33. Mishra Rangnath, Cool Barbara L., Laderoute Keith R., Foretz Marc, Viollet Benoit, Simonson Michael S., AMP-activated Protein Kinase Inhibits Transforming Growth Factor-β-induced Smad3-dependent Transcription and Myofibroblast Transdifferentiation, 10.1074/jbc.m800902200
  34. Schnabl B, The role of Smad3 in mediating mouse hepatic stellate cell activation, 10.1053/jhep.2001.25349
Bibliographic reference Da Silva Morais, Alain ; Abarca-Quinones, Jorge ; Guigas, Bruno ; Viollet, Benoit ; Starkel, Peter ; et. al. Development of hepatic fibrosis occurs normally in AMPK-deficient mice. In: Clinical Science, Vol. 118, no. 6, p. 411-420 (2010)
Permanent URL http://hdl.handle.net/2078.1/29420