Impairment of transforming growth factor beta signaling in caveolin-1-deficient hepatocytes: role in liver regeneration.
Caveolin-1 (Cav-1) is the main structural protein of caveolae and plays an important role in various cellular processes such as vesicular transport, cholesterol homeostasis, and signal transduction pathways. The expression and functional role of Cav-1 have been reported in liver and in hepatocyte cell lines, in human cirrhotic liver, and in hepatocellular carcinomas. Previous studies demonstrated that Cav-1 was dispensable for liver regeneration, because Cav-1(-/-) animals survived and fully regenerated liver function and size after partial hepatectomy. In this study, we have investigated the mechanisms by which the lack of Cav-1 accelerates liver regeneration after partial hepatectomy. The data show that transforming growth factor beta (TGF-beta) signaling is impaired in regenerating liver of Cav-1(-/-) mice and in hepatocytes derived from these animals. TGF-beta receptors I and II do not colocalize in the same membrane fraction in the hepatocytes derived from Cav-1(-/-) mice, as Smad2/3 signaling decreased in the absence of Cav-1 at the time that the transcriptional corepressor SnoN accumulates. Accordingly, the expression of TGF-beta target genes, such as plasminogen activator inhibitor-1, is decreased due to the presence of the high levels of SnoN. Moreover, hepatocyte growth factor inhibited TGF-beta signaling in the absence of Cav-1 by increasing SnoN expression. Taken together, these data might help to unravel why Cav-1-deficient mice exhibit an accelerated liver regeneration after partial hepatectomy and add new insights on the molecular mechanisms controlling the initial commitment to hepatocyte proliferation.
Mayoral
Rafael
R
From the Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Arturo Duperier 4, 28029 Madrid; the Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Villarroel 170, 08036 Barcelona, and.
Valverde
Ángela M
ÁM
From the Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Arturo Duperier 4, 28029 Madrid; the Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Mallorca 183, 08036 Barcelona, Spain.
Llorente Izquierdo
Cristina
C
From the Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Arturo Duperier 4, 28029 Madrid.
González-Rodríguez
Águeda
Á
From the Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Arturo Duperier 4, 28029 Madrid; the Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Mallorca 183, 08036 Barcelona, Spain.
Boscá
Lisardo
L
From the Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Arturo Duperier 4, 28029 Madrid; the Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Villarroel 170, 08036 Barcelona, and.
Martín-Sanz
Paloma
P
From the Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Arturo Duperier 4, 28029 Madrid; the Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Villarroel 170, 08036 Barcelona, and. Electronic address: pmartins@iib.uam.es.
D000818:Animals; D015153:Blotting, Western; D051242:Caveolin 1 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008115:Liver Regeneration / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism
D051242:Caveolin 1; D011518:Proto-Oncogene Proteins; D018125:Receptors, Transforming Growth Factor beta; C486157:Skil protein, mouse; D051899:Smad2 Protein; D051900:Smad3 Protein; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II