Involvement of the Cytosolic Phospholipase A2 alpha Signaling Pathway in Spontaneous and Transforming Growth Factor-beta Induced Hepatic Stellate Cell Activation.
Liena Zhao, Zu-Hua Gao. University of Calgary and Calgary Laboratory Services, AB, Canada
Background: Activated hepatic stellate cells (HSCs) play a pivotal role in liver fibrogenesis. The aim of the study is to evaluate the involvement of cytosolic phospholipase A2 alpha (cPLA2α) signaling pathway in spontaneous and transforming growth factor-beta (TGF-β) induced HSC activation.
Design: Rat HSCs were isolated, purified, cultured, and stimulated with TGF-β1 in the presence or absence of the selective cPLA2α inhibitor, arachidonyltrifluoromethyl ketone (AACOCF3). The activation status of HSC was evaluated by immunofluorescent staining of alpha-smooth muscle actin (α-SMA) and by measuring the expression of cPLA2α, cyclooxygenase 2 (COX-2) and peroxisome proliferator-activated receptor beta/delta (PPAR-β/d) using Western blot analysis.
Results: Rapid and significant increase in the expression of cPLA2α was observed during spontaneous activation of HSCs. These events preceded the elevation of PPAR-β/d and α-SMA. Elevated expression of cPLA2α, but not COX-2, was also observed during TGF-β induced HSC activation. The TGF-β induced α-SMA expression was blocked by the selective cPLA2 inhibitor, AACOCF3. Furthermore, transfection of cPLA2α expression vector enhanced the transcription activity of PPAR- β/d and the expression of α-SMA in HSCs.
Conclusions: These data demonstrated a novel intracellular signaling pathway in spontaneous and TGF-β induced activation of HSCs that involves cPLA2α mediated induction of PPAR-β/d. Therefore, inhibiting this signaling pathway may represent a novel therapeutic approach for the treatment of liver fibrosis.
Category: Liver & Pancreas
Monday, February 28, 2011 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 201, Monday Morning