The Epigenetic Effect of Histone Demethylase LSD1 on Hepatic Steatosis of ApoE Deficient Mice
C Lian, B Lian, M Lisovsky, Y Liu, K Dresser, L Pang, V Ricchiuti, G Williams, G Adler, B Woda, Y Shi. University of Massachusetts, Worcester, MA; Dartmouth Medical School, Lebanon, NH; Brigham & Women's Hospital, Harvard Medical School, Boston, MA
Background: Non-alcoholic fatty liver disease is the most frequent cause of abnormal liver function with a prevalence of 18% in US. The pathogenesis of the condition is poorly understood. Even though the epigenetic mechanism has been increasingly recognized, their role in the pathogenesis of hepatic steatosis is not well defined. Here, we study the effect of histone Lysine Specific Demethylase (LSD1) on diet-induced hepatic steastosis in apoE deficient mice.
Design: All ApoE-deficient mice were fed with a high cholesterol diet containing 42% fat and 1.5% cholesterol from 8 weeks. The control group (n=6) was treated with control GFP-AAV, while the LSD1 knockdown group (n=6) was treated with LSD1 siRNA -AAV. All mice were injected intravenously with the AAV (x1012) at 18 weeks. Blood and liver tissue were collected when the mice were sacrificed at 30 weeks.
Results: Histologically, the liver injury of steatosis with mild inflammation was induced by the diet in the control apoE deficient mice. The liver of siRNA-based LSD1 knockdown mice showed significantly reduced steatosis in comparison to the control mice (p<0.05).
In addition, the expression of pro-inflammatory factors, such as leptin, TNF-α, IL-6 and MCP-1 was significantly decreased in the liver of LSD1 knockdown mice as compared to control (p<0.05). Furthermore, adiponectin expression was markedly increased in LSD1 knockdown mice versus the control mice. These changes of gene expression are correlated with the decrease of steatosis assessed morphologically.
Conclusions: Our data demonstrate that LSD1, a key enzyme of histone regulation, play an important role in hepatic steatosis. By inhibition of LSD1, gene expression of pro-inflammatory factors was reduced and anti-inflammatory adiponectin was increased significantly. These findings are correlated with the reversal of steatosis morphologically in the apoE deficient mice.
Category: Liver & Pancreas
Monday, March 22, 2010 1:00 PM
Poster Session II # 182, Monday Afternoon