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American Liver Foundation
39 Broadway, Suite 2700
New York, New York 10006
Congressman John Joseph Moakley Postdoctoral Research Fellowship
Albert Einstein College of Medicine
Project Title: Defective macrophage autophagy promotes chronic inflammation in NAFLD
Macrophage-mediated inflammation mediates the development of the metabolic syndrome and its associated diseases, including nonalcoholic fatty liver disease (NAFLD). Macrophages can be activated by various stimuli and undergo polarization into proinflammatory M1 or anti-inflammatory M2 macrophages. A preponderance of M1 macrophages promotes tissue inflammation and is present in adipose tissue in obesity related diseases. Central to NAFLD development is an increase in serum free fatty acids (FFAs) and their excessive deposition in tissues. Saturated FFAs can trigger M1 macrophage polarization, suggesting that alterations in the metabolism of these FFAs may modulate the inflammatory response in NAFLD. Previous studies in Dr. Liu’s laboratory have demonstrated that autophagy regulates cellular lipid metabolism by mediating lipolysis which supplies FFAs for β-oxidation. These findings together with the fact that macrophage activation and polarization are mediated by energy provided from oxidative metabolism, led him to postulate that loss of autophagic function triggers the development of NAFLD by promoting proinflammatory macrophage activation and polarization. In this study, Dr. Liu will employ both in vitro and in vivo approaches to examine the role of autophagy in regulating macrophage activation and polarization. First, he will investigate whether inhibition of macrophage autophagy alters macrophage activation and polarization into an M1 or M2 phenotype. Studies will be performed in bone marrow-derived macrophages from mice with a macrophage-specific knockout of the critical autophagy gene atg7 in order to inhibit autophagy, and the mouse macrophage cell line RAW264.7 with a lentiviral atg7 shRNA knockdown. He will examine the activation and polarization of these cells in response to LPS, IFNγ, Th2 cytokines and FFAs. In addition, the macrophage-specific atg7 knockout mice will be fed a high fat diet (HFD) to induce NAFLD and determine whether the loss of autophagy accelerates HFD-mediated inflammation in liver and adipose tissue and the development of steatohepatitis. These studies will delineate a new mechanism for the regulation of the innate immune response in NAFLD, and indicate that manipulation of the autophagic pathway could be a potential therapy in this disease.