title: SPARC (secreted protein acidic and rich in cysteine) knockdown protects mice from acute liver injury by reducing vascular endothelial cell damage.
abstract: Secreted protein, acidic and rich in cysteine (SPARC) is involved in many biological process including liver fibrogenesis, but its role in acute liver damage is unknown. To examine the role of SPARC in acute liver injury, we used SPARC knock-out (SPARC(-/-)) mice. Two models of acute liver damage were used: concanavalin A (Con A) and the agonistic anti-CD95 antibody Jo2. SPARC expression levels were analyzed in liver samples from patients with acute-on-chronic alcoholic hepatitis (AH). SPARC expression is increased on acute-on-chronic AH patients. Knockdown of SPARC decreased hepatic damage in the two models of liver injury. SPARC(-/-) mice showed a marked reduction in Con A-induced necroinflammation. Infiltration by CD4+ T cells, expression of tumor necrosis factor-α and interleukin-6 and apoptosis were attenuated in SPARC(-/-) mice. Sinusoidal endothelial cell monolayer was preserved and was less activated in Con A-treated SPARC(-/-) mice. SPARC knockdown reduced Con A-induced autophagy of cultured human microvascular endothelial cells (HMEC-1). Hepatic transcriptome analysis revealed several gene networks that may have a role in the attenuated liver damaged found in Con A-treated SPARC(-/-) mice. SPARC has a significant role in the development of Con A-induced severe liver injury. These results suggest that SPARC could represent a therapeutic target in acute liver injury.
authors.affiliation: Liver Unit, Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires, Argentina.
authors.forename: E
authors.identifier: 0000000152269747
authors.initials: E
authors.lastname: Peixoto
authors.affiliation: 1] Liver Unit, Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires, Argentina [2] CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Buenos Aires, Argentina.
authors.forename: C
authors.initials: C
authors.lastname: Atorrasagasti
authors.affiliation: 1] Liver Unit, Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires, Argentina [2] CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Buenos Aires, Argentina.
authors.forename: J B
authors.initials: JB
authors.lastname: Aquino
authors.affiliation: Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina.
authors.forename: R
authors.initials: R
authors.lastname: Militello
authors.affiliation: Liver Unit, Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires, Argentina.
authors.forename: J
authors.initials: J
authors.lastname: Bayo
authors.affiliation: Liver Unit, Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires, Argentina.
authors.forename: E
authors.initials: E
authors.lastname: Fiore
authors.affiliation: Liver Unit, Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires, Argentina.
authors.forename: F
authors.initials: F
authors.lastname: Piccioni
authors.affiliation: Molecular and Cellular Therapy Laboratory, Fundación Instituto Leloir, Buenos Aires, Argentina.
authors.forename: E
authors.initials: E
authors.lastname: Salvatierra
authors.affiliation: 1] Liver Unit, Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires, Argentina [2] CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Buenos Aires, Argentina.
authors.forename: L
authors.initials: L
authors.lastname: Alaniz
authors.affiliation: 1] Liver Unit, Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires, Argentina [2] CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Buenos Aires, Argentina.
authors.forename: M G
authors.initials: MG
authors.lastname: García
authors.affiliation: 1] University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [2] Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Bataller
authors.affiliation: CIMA, Universidad de Navarra, Pamplona, España.
authors.forename: F
authors.initials: F
authors.lastname: Corrales
authors.affiliation: 1] Universidad de la Frontera, Temuco, Chile. [2] Universidad Autónoma de Chile, Santiago, Chile.
authors.forename: M
authors.initials: M
authors.lastname: Gidekel
authors.affiliation: Molecular and Cellular Therapy Laboratory, Fundación Instituto Leloir, Buenos Aires, Argentina.
authors.forename: O
authors.initials: O
authors.lastname: Podhajcer
authors.affiliation: 1] CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Buenos Aires, Argentina [2] Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina.
authors.forename: M I
authors.initials: MI
authors.lastname: Colombo
authors.affiliation: 1] Liver Unit, Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires, Argentina [2] CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Buenos Aires, Argentina.
authors.forename: G
authors.initials: G
authors.lastname: Mazzolini
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology / Q000378:metabolism*; D003208:Concanavalin A; D042783:Endothelial Cells / Q000502:physiology*; D004730:Endothelium, Vascular / Q000473:pathology; D055785:Gene Knockdown Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015676:Osteonectin / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome
chemical_list: D008070:Lipopolysaccharides; D015676:Osteonectin; C578250:SPARC protein, mouse; D003208:Concanavalin A