title: Fibronectin Overexpression Modulates Formation of Macrophage Foam Cells by Activating SREBP2 Involved in Endoplasmic Reticulum Stress.
abstract: OBJECTIVE
  To explore the explicit role of fibronectin (FN) isforms in atherosclerotic lesions and the underlying mechanisms.
  
  
  RESULTS
  Inducible stable expression was performed, and similar results were observed between EDA+FN (FN containing EDA domain) and EDA-FN (FN devoid of EDA domain). FN isforms could trigger endoplasmic reticulum (ER) stress, thereby leading to lipid accumulation in cultured Raw264.7 cells. FN isforms-induced gene expression and lipid accumulation were inhibited by a chemical chaperone 4-phenyl butyric acid (PBA) or by overexpression of the ER chaperone, GRP78/BiP, demonstrating a direct role of ER stress in activation of cholesterol/triglyceride biosynthesis. Moreover, activation of the sterol regulatory element binding protein-2 (SREBP2) was found to be downstream of ER stress, and this activation was affirmed to account for the intracellular accumulation of cholesterol using RNAi technique.
  
  
  CONCLUSIONS
  our study suggests that enhanced FN in lesions facilitates foam cell formation due to dysregulation of the endogenous sterol response pathway by activation of ER stress, and confirms that EDA+FN has no more pro-atherogenic role than EDA-FN in triggering ER stress.
authors.forename: Hansong
authors.initials: H
authors.lastname: Du
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhengfeng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002460:Cell Line; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D005353:Fibronectins / Q000378:metabolism*; D005487:Foam Cells / Q000166:cytology*; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D005353:Fibronectins; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2