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.

Smoc2 potentiates proliferation of hepatocellular carcinoma cells via promotion of cell cycle progression

“…Previous results showed that Smoc2 plays an important role in promoting G1/S progression through participating in the maintenance of cyclin D1 expression[34-36]. In other words, cyclin D1 can be considered as an effector of Smoc2-induced DNA synthesis[37,38]. …”

SPARC gene deletion protects against toxic liver injury and is associated to an enhanced proliferative capacity and reduced oxidative stress response

“…Liver damage of different causes induces secreted protein, acidic and rich in cysteine (SPARC) expression [1–5]. SPARC has the ability to induce a positive feedback with transforming growth factor beta (TGF-β)-1, stimulates collagen deposition, induces inflammation, and has anti-proliferative properties.…”

“…SPARC has the ability to induce a positive feedback with transforming growth factor beta (TGF-β)-1, stimulates collagen deposition, induces inflammation, and has anti-proliferative properties. We have previously demonstrated that downregulation of SPARC has the capacity to reduce acute liver damage after concanavalin A (ConA) administration [5], and the degree of fibrosis in tioacetamide (TAA) and bile duct ligation models [5, 4]. The mechanistic role of SPARC in liver pathologies has not been addressed, although our previous works demonstrated that SPARC −/− mice treated with ConA showed reduction in T CD4 + lymphocytes infiltration, tumor necrosis factor alpha (TNFα) production, and apoptosis.…”

“…The mechanistic role of SPARC in liver pathologies has not been addressed, although our previous works demonstrated that SPARC −/− mice treated with ConA showed reduction in T CD4 + lymphocytes infiltration, tumor necrosis factor alpha (TNFα) production, and apoptosis. SPARC knockdown of human microvascular endothelial cells (HMEC-1) showed reduced ConA-induced autophagy and apoptosis [5]. In two fibrogenic models generated by TAA administration and by bile duct ligation, SPARC −/− mice showed a reduction in the degree of inflammation, deposits and expression levels of collagen, and in the number of activated myofibroblasts [4, 7].…”

The Reactive Oxygen Species–Mitophagy Signaling Pathway Regulates Liver Endothelial Cell Survival During Ischemia/Reperfusion Injury

“…ROS generation is a key regulator of liver IRI and was until recently viewed as the primary driver for parenchymal cell death during IRI, but more recent studies demonstrate that ROS is cytoprotective through its activation of the cellular process of autophagy . Indeed, autophagy activation has been shown to limit injury following a variety of acute liver injuries, and its role in regulating liver IRI is attracting growing attention . Limited studies have explored the role of ROS‐dependent autophagy during IRI, but the relationship between ROS and autophagy in LEC during IRI is not known.…”