This application outlines a comprehensive five-year mentored training program with a transition to independence. The application investigates the role of ceramides in insulin resistance in early alcoholic liver disease (ALD) and will be carried out in the laboratory of Dr. Rexford Ahima, M.D., Ph.D., Professor of Medicine, Division of Endocrinology, Diabetes, &Metabolism;Director of Obesity Unit, Institute for Diabetes, Obesity and Metabolism (IDOM);and Director of Diabetes and Endocrinology Research Center Mouse Phenotyping, Physiology and Metabolism Core. The research plan explores the novel hypothesis that Perilipin 2 (Plin2)- mediated lipid droplet biogenesis and adiponectin signaling are critically involved mechanistically in ceramide metabolism and insulin sensitivity in alcoholic steatosis. This hypothesis will be pursued by the following interrelated Specific Aims: (1) To determine if inhibition of ceramide synthesis or Plin2 expression ameliorates insulin resistance in alcoholic steatosis in vivo. (2) To determine whether ceramide's impairment of insulin signaling is mechanistically mediated by Plin2 in ethanol-treated hepatocytes. and (3) To determine if AMPK and ceramidase activation are required for adiponectin's regulation of ceramides and Plin2 in alcoholic steatosis. To accomplish these Specific Aims, we will use a combination of comprehensive in vivo metabolic phenotyping, lipidomics analyses, and in vitro modeling approaches, including the use of genetic knockout models. Successful accomplishment of these Specific Aims will identify specific molecular targets of insulin signaling in alcoholic steatosis which may lead to the development of new therapeutics for ALD. Concurrently, I will complete a career development program under the guidance of an advisory committee with internationally recognized NIH-funded researchers from the University of Pennsylvania and Thomas Jefferson University. This structured program combined with clinical experience in hepatology that focuses on the management of fatty liver diseases will make me uniquely positioned to become a leading physician-scientist capable of NIH-funded independent investigation at a leading academic center. I plan to oversee my own laboratory and research program focused on developing a lipid signature that can be used to predict disease prognosis in patients with both ALD and non-alcoholic fatty liver and identify insulin signaling targets that can ultimately be used therapeutically.
Alcoholic liver disease is a major cause of liver disease worldwide and can lead to liver failure, liver cancer and death. It is a major public health problem and costs billions of dollars in healthcare expenditures annually in the United States. There are no medications to prevent the progression of alcoholic liver disease and alcohol cessation is difficult to achieve in many patients. Therefore, identifying ways to prevent worsening disease is critical. Patients with alcoholic liver disease who develop a resistance to the body's normal levels of insulin (insulin resistance) are more likely to have worse disease. Our application investigates how a substance called ceramide impairs the liver's ability to respond to insulin and so causes insulin resistance. Understanding how this substance causes insulin resistance may lead to new therapeutics in order to prevent disease progression in alcoholic liver disease.
|Carr, Rotonya M; Peralta, Giselle; Yin, Xiaoyan et al. (2014) Absence of perilipin 2 prevents hepatic steatosis, glucose intolerance and ceramide accumulation in alcohol-fed mice. PLoS One 9:e97118|